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Novel Discourse | Thread: Previous Bookmark Forum index Next | ![]() |
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Posts 16 - 30 of 36 | Subject: alpha-benzylpiperidine & alpha-piperonylpiperidine | Page: Previous First All Last Next New | Down | ![]() |
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longimanus (Hive Bee) 09-02-04 01:24 No 528954 ![]() |
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2-benzylpiperidine search before bedtime | Bookmark Reply | |||||
Searching the Combined Chemical Dictionary for 2-benzylpiperidines with MW < 350 revealed 5 interesting compounds. Two of them are very well known - methylphenidate and pipradrol. The other three: Phenyl-2-piperidylmethanol - antidepressant, anorexic agent; the O-Ac derivative of the (-)-threo-form is called Levofacetoperane or Phacetoperane, the hydrochloride - Lidepran with LD50(rat, orl) 400 mg/kg and LD50(rat, inv) 80 mg/kg. Rimiterol (α-(3,4-Dihydroxyphenyl)-2-piperid Difemetorex (2-(Diphenylmethyl)-1-piperidineethanol) That`s all for now. Tomorrow there will be results for 3-phenylpiperidine - and I`m sure they`ll be rather interesting ![]() |
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Rhodium (Chief Bee) 09-03-04 19:14 No 529371 ![]() |
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2-Diphenylmethyl-Piperidine: Synthesis & Effects (Rated as: excellent) |
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Zentralerregende Wirkung eines neuen Piperidinderivates J. Tripod, E. Sury, K. Hoffmann Experentia 10, 261-262 (1954) (https://www.rhodium.ws/pdf/diphenylmeth Abstract A new piperidine derivative, the 2-diphenylmethyl piperidine already in doses of 0.001 g/kg s.c. strong increase of the spontaneous motility of various animals. On mice it has about the same potency as desoxy-ephedrine and is about 3 times more potent than amphetamine. It also acts markedly antagonistic on various narcotics but has practically no peripheral sympathomimetic effects. ____ ___ __ _ Über Alkylenimin-Derivate. II. Mitteilung. Piperidin-Derivate mit zentralerregender Wirkung. I. E. Sury und K. Hoffmann Helv. Chim. Acta. 37, 2133-2145 (1954) (https://www.rhodium.ws/pdf/diphenylmeth Abstract A series of new piperidine derivatives substituted in the 2-position has been prepared and tested pharmacologically. Most of these compounds have central stimulating effects, above all the 2-diphenylmethyl-piperidine hydrochloride. The Hive - Clandestine Chemists Without Borders |
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Rhodium (Chief Bee) 09-08-04 21:40 No 530333 ![]() |
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α,α-Disubstituted 2-Piperidinemethanol (Rated as: good read) |
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Central Stimulants. α,α-Disubstituted 2-Piperidinemethanols and 1,1-Disubstituted Heptahydrooxazolo[3,4-a]pyridines Frederick J. McCarty, Charles H. Tilford, M. G. Van Campen J. Am. Chem. Soc. 79, 472-480 (1957) (https://www.rhodium.ws/pdf/diphenyl-2-p Abstract A series of α,α-disubstituted-2-pyridineme The Hive - Clandestine Chemists Without Borders |
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Lego (Hive Bee) 09-09-04 17:00 No 530494 ![]() |
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Metabolism and analysis of PPP/MPPP/MPHP (Rated as: excellent) |
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Metabolism of the new designer drug alpha-pyrrolidinopropiophenone (PPP) and the toxicological detection of PPP and 4'-methyl-alpha-pyrrolidinopropiophenone Dietmar Springer, Giselher Fritschi and Hans H. Maurer J. Chrom. (B), 2003, 796(2), 253-266 Medline (PMID=14581066) Abstract: R,S-alpha-pyrrolidinopropiophenone (PPP) is a new designer drug with assumed amphetamine-like effects which has appeared on the illicit drug market. The aim of this study was to identify the PPP metabolites using solid-phase extraction, ethylation or acetylation as well as to develop a toxicological detection procedure in urine using solid-phase extraction, trimethylsilylation and gas chromatography-mass spectrometry (GC-MS). Analysis of urine samples of rats treated with PPP revealed that PPP was extensively metabolized by hydroxylation of the pyrrolidine ring with subsequent dehydrogenation to the corresponding lactam, hydroxylation of the aromatic ring in position 4' or double dealkylation of the pyrrolidine ring to the corresponding primary amine (cathinone) partly followed by reduction of the keto group to the corresponding secondary alcohol (norephedrines). As cathinone and the norephedrine diastereomers are also formed after intake of other drugs of abuse or medicaments, special attention must be paid to the detection of the unequivocal metabolite 2"-oxo-PPP as an unambiguous proof for the intake of PPP. The hydroxy groups were found to be partly conjugated. Based on these data, PPP could be detected in urine via its metabolites by full-scan GC-MS using mass chromatography for screening and library search for identification by comparison of the spectra with reference spectra. The same toxicological detection procedure can be applied to other designer drugs of the pyrrolidinophenone type, like MOPPP, MDPPP, MPHP, and MPPP. The detection of the latter will also be presented here. ______ _____ ____ ___ __ _ Studies on the metabolism and toxicological detection of the new designer drug 4'-methyl-alpha-pyrrolidinopropiophenone Dietmar Springer, F. Peters, Giselher Fritschi and Hans H. Maurer J. Chrom. (B), 2002, 773(1), 25-33 Medline (PMID=12015267) Abstract: 4'-Methyl-alpha-pyrrolidinopropiophenone ______ _____ ____ ___ __ _ New designer drug 4'-methyl-alpha-pyrrolidinohexanophenone Dietmar Springer, F. Peters, Giselher Fritschi and Hans H. Maurer J. Chrom. (B), 2003, 789(1), 79-91 Medline (PMID=12726846) Abstract: R,S-4'-Methyl-alpha-pyrrolidinohexanophe The tendency is to push it as far as you can |
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scarmani (Hive Bee) 09-10-04 14:31 No 530624 ![]() |
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Rehash of Stimulant Stuctures (Rated as: excellent) |
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Please excuse, A lot of my post will be repeat material / (plagiarised from other posts). Also not all of it has to do with the main topic of the thread. However in this post there are structures of heterocyclic stimulants that relate to this thread a greater or lesser degree (e.g. Phacetoperane). It might be useful to have the diagrams of various non-conventional stimulants in one place (along with a brief description), and be able to spin them skeletons around with the mouse (unless the structures crash the molecule viewer and I have to post a flat picture instead!). Also I think there are a couple structures here that weren't yet mentioned too much elsewhere. Molecule: diphenyl(piperidin-2-yl)methanol ("OC(C2=CC=CC=C2)(C3=CC=CC=C3)C1NCCCC1") aka Pipradol, aka Meratran. The "parent" compound. This is legally restricted in sports competition and some countries for modest abuse potential. Sold in tonic. "Marketed in 1956. Considered to be a mild central nervous system stimulant. Occasionally overstimulation reported. Has been studied in depressive mood. Dosage 1 - 3mg/day." http://home.intekom.com/pharm/adcock/ale http://www.psychotropics.dk/alphaindex/v The compound without the alcohol group, 2-diphenylmethyl piperidine, has also been mentioned in the paper: "in doses of 1 mg/kg s.c. produces a strong increase of the spontaneous motility of animals. On mice it has about the same potency as methamphetamine and is about 3 times more potent than amphetamine but has practically no peripheral sympathomimetic effects". Also pointed out in 'Future Drugs of Abuse': "A best bet for a future CsA is the most potent adrenomimetic compound in this series, 2-diphenylmethylpiperidine." Molecule: (R)-(+)-alpha,alpha-Diphenyl-2-pyrrolidi This is obviously a close analog of pipradol. One Hive post said "5-10 mg lasts hours, but not fun", another said "20 mg of the (R) isomer (orally) provides quite a mild, but prolonged stimulation (12 hours) which is quite similar to about 30-40mg of methylphenidate... 20mg IM is 1.5 to 2x oral potency, but it's a lot more euphoric. It also has very little peripheral actions (no heart pounding out of your chest & very little dry mouth)." Apparently works by Dopamine Reuptake Inhibition, like cocaine. DAT uptake inhibition: Ki is 170 nM vs Cocaine 200 nM Molecule: (4-(1,2-diphenylethyl)pyridine ("C1(CC(C3=CC=CC=C3)C2=CC=NC=C2)=CC=CC=C Another similar structure; This was from the thread containing Post 475625 (silenziox: "18 & 23 Cas numbers???", General Discourse) Another Monoamine Reuptake Inhibitor; it has test tube potency comparable to cocaine (but not aware of any bioassays): DAT Uptake Inhibition: Ki is 263 nM; 5HT Uptake Inhibition: Ki is 910 nM; NE Uptake Inhibition: Ki is 393 nM Molecule: 2-benzhydryl-3-methoxy-1-methylpiperidin Substituted 2-diphenylmethylpiperidine has similar potency: "Minimal cardiac and respiratory effects at stimulant doses and was tried clinically. It was a potent stimulant, but the dose-response effect was too marked. At a given dose, due to the variation in the individual patient response, the level of stimulation attained frequently was above or below that desired." Stimulant at 1 mg/kg ip. N-desmethyl analog: Stimulant at 0.3 mg/kg" Molecule: alpha,alpha-diphenyl-3-morpholinemethane Fastandbulbous states it's a stimulant (DAT inhibitor, as is methylphenidate and cocaine), but it was found to be active at a much lower dose than the other two, (reckoned to be 0.5 - 1mg in man). Lillienthal listed the reference for the synthesis on his references page: Central Stimulants. Cyclized Diphenylisopropylamines Stanley O. Winthrop and Leslie G. Humber, J. Org. Chem. 26(8), 2834-2836 (1961) Molecule: 3-methyl-2-phenylmorpholine ("CC(NCCO2)C2C1=CC=CC=C1") Phenmetrazine, aka Preludin. A post on the Hive says "Apparently you have to inject phenmetrazine to feel it's true euphoria... When you do that it apparently kicks amphetamine's ass. It was abused much in Sweden in the 60-70s". Oral dosage 50mg 2-3 times a day. Another post states "stimulate the release of Norepinephine like U4Euh does; notice the structural similarity also". Paper says "One widely used approach for the synthesis of new compounds that possess some type of central nervous system stimulant activity is the cyclization of substituted phenethanolamines into heterocycles, such as morpholine, piperidine, and 2-oxazoline in such a manner that more or less of the phenethanolamine skeleton becomes part of the heterocyclic ring. Well-known drugs of this type are phenmetrazine. pipradol, and anminorex." Post 429511 (alphacentauri: "Phenmetrazine", Stimulants) Molecule: Phenyl-2-piperidylmethanol ("OC(C2=CC=CC=C2)C1NCCCC1") aka Phacetoperane: antidepressant, anorexic agent. "Shulgin (1975) suggested that levophacetoperane could well be a future clandestine CsA. However, this compound shares the same limitation as methylphenidate, in that only one diastereoisomer is active; and it is less potent than methylphenidate" Again has the phenethanolamine in heterocycle. Molecule: 1-(1-benzylbutyl)pyrrolidine ("CCCC(N2CCCC2)CC1=CC=CC=C1") "Prolintane hydrochloride is a mild central stimulant and has properties similar to those of dexamphetamine. Peak plasma level 1 to 2 hours after single dose. Elimination half-life about 2 hours." There is also the closely related Pyrovalerone: Molecule: 4'-methyl-2-(1-pyrrolidinyl)valerophenon "Pyrovalerone, Studied as psychostimulating agent in the management of asthenic and depressive states with mental exhaustion." These two above (prolintane and pyrovalerone) could be called the "parent" molecules for the pyrrolidinopropiophenones posted above, synthesized by Nemo Tenetur. Molecule: 4-(4-chlorophenyl)-1-methyl-3-propylpipe This molecule could be considered a piperidine based cocaine analog (or more closely, phenyltropane analog) It is mentioned in https://www.rhodium.ws/pdf/cocaineanalog Binding to DAT (cis isomer): Ki 3.0 nM; DAT Inhibition (cis isomer): Ki 8.3 nM Molecule: (S)-methyl 2-(3,4-dichlorophenyl)-2-((S)-piperidin- Here is a halogenated Methylphenidate analog with greater potency than the parent compound (mentioned in the same review paper as the piperidine derivative above.) DAT Binding: Ki 5.3 nM; DAT Inhibition: Ki 7.0 nM Molecule: 3-(3,4-dichlorophenyl)-N-methyl-1-indana aka Indatraline, Lu 19-005 According to preliminary investigations, potential antidepressant agent. Very long-lasting and potent cocaine-like stimulant, self administered in monkeys but with long intervals in between, because of long duration of action. Produces stereotypies, weight loss, anemia similar to those caused by chronic high-dose cocaine. Combines an equally potent inhibitive effect on dopamine, norepinephrine and serotonin. Molecule: 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydr aka Diclofensine. NE/5-HT/DA uptake inhibitor. Psychostimulating and mood elevating agent. Double-blind clinical trials in the treatment of depressions and dysphoric mood. Minor anticholinergic effects. Dosage 25 to 150mg/day. Plasma half-life in healthy subjects about 4 hours. Related to Nomifensine, which itself had recreational and motivating potential and which many people liked before it was removed from the pharmaceutical market. 1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1 ![]() aka DOV 21,947. For some reason this bicyclic structures seems to crash the molecule viewer. Inhibits the reuptake of serotonin, norepinephrine, and dopamine (IC50 values of 12, 23, and 96 nM, respectively). DOV 21,947 reduces the duration of immobility in the forced swim test (using rats) with an oral minimum effective dose of 5 mg/kg. This antidepressant-like effect manifests in the absence of significant increases in motor activity at doses of up to 20 mg/kg. DOV 21,947 also produces a dose-dependent reduction in immobility in the tail suspension test, with a minimum effective oral dose of 5 mg/kg. Although this may not be a locomotor stimulant it looks like an interesting / promising antidepressant, also it has the similar structural features of this thread. Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor Phil Skolnicka, Piotr Popikb, Aaron Janowskyc, Bernard Beera, Arnold S. Lippa, European Journal of Pharmacology. 461, 99–104 (2003) DOI:10.1016/S0014-2999(03)01310-4 ______ _____ ____ ___ __ _ As a side note: there seem many stimulant molecules where the 4-halogen or the 3,4-halogen on the phenyl confers added potency. 4-fluoroamphetamine seems to be an interesting variation on amphetamine with slightly more sertonergic character. I wonder if 3,4-fluoroamphetamine would be even more serotonergically interesting. Which brings to mind (getting totally off track,) I think 3-methoxy-4-ethoxyamphetamine would be like MDA / MDMA. Look at pihkal 123 (MEPEA, 3-methoxy-4-ethoxyphenethylamine, lightly active at 300 mg "The effects were very quiet, very pleasant, and very light. There was nothing psychedelic here, but rather a gentle lifting of spirits") compared to pihkal 115 (MDPEA, 3,4-methylenedioxyphenethylamine, inactive at 300 mg). It stands to reason that the already-active MEPEA would become more potent and empathogenic effects accentuated as it followed the analogous path from MDPEA to MDA to MDMA. Also ME (metaescaline, 3,4-dimethoxy-5-ethoxyphenethylamine) seems to exhibit some "empathogenic" qualities, maybe the 3-ethoxy-4-methoxy-amphetamine would also. Additional interesting to look at would be MEA 3-methoxy-4-ethylamphetamine, similar to 3-methoxy-4-methylamphetamine MMA, and 3-methoxy-4-bromoamphetamine (with the last few, have to be careful of PMA trouble or PCA neurotoxicity of course). ______ _____ ____ ___ __ _ N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-a ![]() aka Fencamfamine. From the Hive "I have heard from a talented friend of mine who has exceptional taste that fencamfamine is his favorite stimulant of them all..." and another post mentioned "Fencamfamine (FCF) is a CNS stimulant that works by blockading dopamine reuptake and it has a potency similiar to amphetamine. Well that's what i was told by my coach who sold it to me, lol! I took a 0.5g IV dose for a research experiment once, that produced a very clean & subtle buzz which lasted for about 4-5 hours from memory. Nothing special, but I found sex was far more pleasurable using FCF as opposed to rooting on meth." Adding halogen 4 or 3,4 on the phenyl may further increase potency. methyl 3-(4-bromophenyl)-8-methyl-8-aza-bicyclo ![]() aka RTI-51 (para-iodo is RTI-55, equally potent). These are basically the most potent 3-phenyltropanes, with description of effects very similar to indatraline (very long lasting (16 h), very potent, reinforcing, locomotor stimulant, and substitute for cocaine). "During the first 2 h of behavioral observation that followed the intraperitoneal (IP) administration of the compound, each of the 3-phenyltropane analogs and cocaine increased horizontal activity). Cocaine, at 30.0 and 56.0 mg/kg, produced significantly greater activity than saline, with a peak effect at approximately 36 000 counts; RTI-51, at 0.49 mg/kg, significantly increased activity to 51 000 counts. RTI-51 (0.49 mg/kg) had an AUC significantly greater than that of 3.0 mg/kg cocaine. When the peak of the activity time course of the phenyltropane analogs were compared with that of cocaine, only 0.49 mg/kg RTI-51 produced a significantly greater peak effect than 3.0 mg/kg cocaine did. In rats, RTI-55 increased extracellular dopamine levels in the nucleus accumbens to about 350% of control values." Molecule: R-1-(Benzofuran-2-yl)-2-propylaminopenta aka (-)-BPAP. This compound is extremely interesting, has a number of unique activities and all of them positive. Also quite potent. Is not only catecholaminergic and serotonergic activity enhancer, but also a norepinephrine and dopamine uptake inhibitor and a weak serotonin uptake inhibitor, without adverse MAOI hypertensive crisis potential. [3H]dopamine, [3H]norepinephrine, and [3H]serotonin uptake IC50 were 42 nM, 52 nM, and 640 nM respectively; thus the effects of (-)-BPAP on dopamine and norepinephrine uptake were more potent than those of cocaine, while its potency at inhibiting serotonin uptake was weaker than that of cocaine. The uptake inhibitory effect of (-)-BPAP may be involved in motor stimulant effects in addition to its Catecholamine Enhancing and Serotonin Enhancing effect. In normal non-habituated rats, BPAP HCl increased motor activity during the entire 2-h observation period. Post 211596 (Rhodium: "BPAP, a catecholamine activity enhancer", General Discourse) Molecule: 7-benzyl-1-ethyl, 4-oxo 1,8-naphthyridine-3-carboxylic acid ("O=C(C1=CN(CC)C2=C(C=CC(CC3=CC=CC=C3)=N aka amfonelic acid; cocaine-like stimulant with apparently very euphoric or addictive qualities. The rats go absolutely nuts for this one. Interesting that this stimulant looks unlike most other stimulant families, although still has phenalkylamine skeleton. In fact it is more closely related to antibacterial compounds. Should be pretty potent in humans, maybe 10 mg or less. DA, NE, 5HT Uptake Inhibition: 7.2 nM, 41.1 nM, 879 nM 1-(1-(benzo[b]thiophen-2-yl)cyclohexyl)p ![]() aka BTCP. This is a PCP analog but instead of being a dissociative it is a very specific cocaine-like stimulant compound, like amfonelic acid. The rats love this compound too. However, there are some health problems observed after repeated i.p. injections. In vivo Potency is comparable to cocaine; active metabolites may contribute to in vivo effect. "The reinforcing actions of BTCP were compared to those of cocaine at equimolar concentrations in drug-naive rats. Two doses (0.125 and 0.25 mg/infusion) that produced reliable self-administration in all the animals for cocaine and BTCP were then tested on a progressive-ratio schedule. At each dose, BTCP supported higher breaking points (BPs) than cocaine. The results demonstrate that rats readily acquire responding maintained by BTCP and suggest that BTCP may have greater reinforcing effects than cocaine at equimolar concentrations." DA-uptake inhibition: IC50 11 nM vs. 296 nM for cocaine Further Studies of the Structure-Activity Relationships of 1-[1-(2-Benzo[b]thienyl)cyclohexyl]piper Xiao-shu He, Lionel P. Ramon, Mariena V. Mattson, Mohyee E. Eldefrawi and Brian R. de Costa, J. Med. Chem. 36(25), 4075-4081 (1993) Also Post 99112 (beagle boy: "Re: PCP Synthesis", Chemistry Discourse) beagle boy said: "The cpd was synthesized (not by me of course) and bioassayed by vaporizing and inhaling it in very small quantities (again, not by me). No effects were apparent, but in retrospect the amounts assayed were quite small, maybe on the order of 10-20 mgs or so." Post 435648 (pHarmacist: "BTCP - a compound with cocaine-like properties", Novel Discourse) Two nice refs by pHarmacist Post 507205 (7is: "More PCP related studies", Methods Discourse) Some more nice refs by 7is 1-(benzo[b]thiophen-2-yl)-N-propylcycloh ![]() This BTCP analog might be about 2x more potent than BTCP based on binding and DAT inhibition. DA-uptake inhibition: IC50 5 nM I have some more relevant references for these notes but I am too tired (read lazy) to retrieve them, check if they've been posted already, upload them, type up the reference in the proper format, and place them next to the appropriate location. This post is, even without them, a spacewasting bewhhymouth. If references are desired, I'll do what I can, if I can, when I can, and where I can (probably a subsequent post). Which, by the way, I live in a can -- and can openers are the definite alphanumerical warnings. Which is to say, watch out for metallic indentations, the sky might crack open and blaze terrible light at any moment. What they didn't tell you about judgement day is that you get et. boot from the shadow of a broken mirror |
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cattleprodder (Hive Bee) 09-11-04 12:33 No 530827 |
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wow, this is getting interesting. | Bookmark Reply | |||||
scarmani, excellent and informative post!!! Nicodem, sorry for my shoddy adaptation of a part of the synthesis for DOAM found in _PiHKAL_ to a totally different compound. I don't really have easy access to many journals where I live now, but all these piperidyl stimulants have really peaked mine, and I hope yours and some other peoples', interest. In particular, scarmani's mention of phacetoperane (phenyl-2-piperidylmethanol) caught my eye. Although I know I am risking sounding like the village chemistry idiot for not knowing the answer to this simple question already, I'm going to ask it anyway: Structurally (pseudo)ephedrine is to methamphetamine as phacetoperane is to 2-benzylpiperidine. Namely, the removal of the benzylic hydroxyl group of each of the former compounds leads to the latter drugs. Phacetoperane, while (mildly) controlled in 1st world countries for being a stimulant, is easily obtainable from overseas; a simple Google search showed me this in a matter of minutes. Now, here's the big if. Can commercially available phacetoperane hydrochloride be reduced with red phosphorous and iodine to yield 2-benzylpiperidine (2-BzP)? I don't see why not, but I am no expert (yet). ;) Nicodem, if not, then what article do you need to have looked up for adaptation to a possible 2-BzP synthesis? I think I could tell from one of your posts, but I want to be sure before trekking over the river and through the woods to the university library and then digging through the ponderous scientific literature for hours on end with no guarantee of finding the article to begin with. Please be specific if you can. Thanks. Scarmani mentions that phacetoperane faces the same limitations as methylphenidate in that only one of its isomers is active. Well, that is no big deal; just ingest twice as much. Only one of the isomers of methamphetamine is active, but there are seemingly millions of satisfied tweakers nonetheless, right? The other negative thing mentioned was the phacetoperane is weaker than Ritalin. However, upon removal of the hydrophilic -OH group, I have a feeling 2-BzP is going to by VERY active. This is due to the much more lipophilic properties of 2-BzP compared to phacetoperane. Again, the comparison to (pseudo)ephedrine and methamphetamine comes to mind, another blood-brain barrier issue. In that case at the very least, the reduction of the alcohol makes a difference as big as night from day. Only time will tell, with the help of some chemical and pharmacological pioneering, if I'm right about 2-BzP. We are the guinea pigs. Cheers. The fact that Shulgin first suggested that levophacetoperane might one day become a future drug of abuse only strengthens my resolve to test 2-BzP (which could also be named phenyl-2-piperidylmethane I suppose) for central nervous system activity in humans. "Get busy, child!"--The Crystal Method |
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Nicodem (Hive Bee) 09-11-04 15:08 No 530838 ![]() |
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Cattleprodder, I'll reply just quickly | Bookmark Reply | |||||
Yes, phacetoperane can be reduced with RB/I method just like ephedrine. About the activity of 2-benzylpiperidine I know nothing. The reason is that stimulants are not off my interest - that's why I said to check Medline yourself. I don't know exactly what to do with stimulants (except maybe as a study aid). Anyway, from what I understood phacetoperane is exactly a "desphenyl pipradol" and since pipradol does not act by the same mechanism as (meth)amphetamine I would say that removing the -OH group might not lead to a more potent stimulant. But like I said this is not my area anymore so you should check the difference in activity of pipradol and its deshydroxy analogue. Scarmani should know better on this subject. BTW, that was a great review he prepared. Wish there would be more posts like that one. “The real drug-problem is that we need more and better drugs.” – J. Ott |
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cattleprodder (Hive Bee) 09-11-04 18:33 No 530858 |
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Nicodem, I agree with your quote that we need... | Bookmark Reply | |||||
Nicodem, I agree with your quote that we need to solve the problem of more and better potential drugs, especially unscheduled ones like 2-piperonylpiperide and 2-benzylpiperidine whose precursors are relatively uncontrolled because they are so obscure. I'm sorry you don't like stimulants, but I f-ing love them, that's why I'm so excited about stumbling on this seemingly idiot proof synth of 2-benzylpiperidine from commercially available online Chinese phacetoperane hydrochloride, red phosphorous and iodine. Rhodium, you have always been my hero(ine), will you be the first to synth and bioassay this easily made stimulant? I am truly not able, for many reasons. As for you, Nicodem, I'll leave the challenge of coming up with a synth for 2-piperonylpiperidine in between your time studying for finals. You are clearly intelligent enough; in fact, you seem like a real chemistry professor to me. I appreciate your input. PLUR (Peace Love Unity Respect) and BURP (Bring Us Real Pills), the cattleprodder (official Hive gadfly) |
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longimanus (Hive Bee) 09-11-04 21:47 No 530897 ![]() |
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some facts and some guesses | Bookmark Reply | |||||
1st - when I said tomorrow I lied (it`s obvious), excuse me. And one of the results I was going to post was 1-phenyl-3-azabicyclo[3.1.0]hexane. Yes, it`s very similar to DOV 21,947. And it`s analgesic; I don`t know what kind of analgesic (narcotic or NSAID or whatever). Further information will be welcomed (read "please, post something!!!"). cattleprodder - why do you suggest
Just guessing? Let me remind you that there are 2 asymmetric carbon atoms => 4 forms (just like ephedrine, not methamphetamine). But that doesn`t mean that the dose should be 4x, maybe more like 2.342617x. |
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scarmani (Hive Bee) 09-12-04 15:05 No 531003 ![]() |
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A few more comments | Bookmark Reply | |||||
Phacetoperane is actually the acetate ester of phenyl-2-piperidinemethanol, but the presumption would be that the ester is metabolically removed. I think Nicodem might be right -- 2-benzylpiperidine would probably not be more potent relative to phacetoperane; by analogy to pipradol and related compounds, the hydroxyl group seems to increase potency. However it does seem likely that 2-benzylpiperidine would have activity, although given the simple structure I think it would be mentioned more in the literature if it was anything particularly notable. As an aside, if anyone is in an adventurous testing mood, 2 and 3 phenyl and benzyl pyrrolidines look directly available without the need for synthesis. http://forums.lycaeum.org/cgi-bin/ultima One pipradol-like stimulant subfamily I didn't mention above was: https://www.rhodium.ws/chemistry/diarylp Molecule: 1-methyl-4,4-diphenylpiperidine ("CN1CCC(C2=CC=CC=C2)(C3=CC=CC=C3)CC1") Also just to note that many substituted 4-phenylpiperidines are scheduled as narcotics (opioids) belonging to the pethedine / prodine family. boot from the shadow of a broken mirror |
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Sedrick (Stranger) 09-13-04 00:02 No 531057 |
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A Good Read | Bookmark Reply | |||||
One of the molecules you have drawn is very similar to the structure of Zoloft. That thioindole containing pcp derivative also looked like a fancy heteroaromatic entity. I could see that one being enjoyable. |
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Fastandbulbous (Hive Bee) 09-14-04 09:33 No 531237 ![]() |
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A lot more potential stimulants (Rated as: excellent) |
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First of all, I’d like to correct a mistake in my previous post (as Scarmani did, but I thought I’d best point it out). The 0.5-1mg dosage referred to 3-(alpha,alpha-diphenylmethyl)morpholine In addition to the excellent post by Scarmani, there are a few additions to the list of active structures. These are all compounds based on the phenethylamine skeleton, and do not cover the phenyltropane groups etc. Most are definitely active (at least as appetite suppressants), but a few stem from a logical extension of known active compounds, using simple measures such as substituting a sulphur atom for an oxygen atom. In order to arrange them in groups, I have classified them as follows: 2-Benzylpiperidine derivatives Phenmetrazine derivatives Alicyclic and oxygen heterocyclics Other nitrogen heterocyclics. Most can be found in assorted journals, but a few come from the work I did for my M.Sc. (SAR of anorectic agents), which was included in a larger paper written by a couple of people who had been lecturers during my undergraduate years (I was eventually relegated on said paper to an et al!). For the names of the following, I have used the approved drug name for compounds that have had some clinical use (because I’m lazy!). Ones marked with an * are ones that should theoretically have activity, but could not be found by searching (a limited number of) journals. 2-Benzylpiperidine derivatives ![]() 1 – 2-benzylpiperidine* 2 – methylphenidate 3 – levophacetoperane 4 – pipradrol 5 – alpha,alpha-diphenyl-2-piperidinemethane 6 - alpha,alpha-diphenyl-2-pyrrolidinemethan 7 - alpha,alpha-diphenyl-2-pyrrolidinemethan 8 - alpha,alpha-diphenyl-3-morpholinemethane 9 – alpha-phenyl-alpha-(2-thienyl)- 2-piperidinemethane* 10- 3-benzylmorpholine* 11- methyl alpha-phenyl-alpha-(3-morpholino)acetate 12- alpha-phenyl-alpha-(3-morpholino)methano Phenmetrazine derivatives ![]() 1 – phenmetrazine 2 – 3,6-dimethyl-2-phenylmorpholine 3 - 3,5-dimethyl-2-phenylmorpholine* 4 – 3-methyl-2-phenylmorpholine-6-one 5 - 3-methyl-2-phenylthiomorpholine* 6 – phenmetramide 7 - 3-methyl-2-(2-thienyl)morpholine* 8 – phendimetrazine 9 – ring substituted phenmetrazine* Alicyclic and oxygen heterocyclics ![]() 1 – fencamfamine 2 – tranylcypromine 3 – 2-phenylcyclopentylamine 4 - 2-phenylcyclohexylamine 5 – 3-amino-2-phenyltetrahydropyran* 6 – 2-aminoindane 7 – 2-aminotetralin 8 – 3-aminochroman* Other nitrogen heterocyclics ![]() 1 – 2-methyl-3-phenylquinuclidine 2 – 2-methyl-3-phenylpiperidine 3 - 2-methyl-3-phenylpyrrolidine* 4 – alpha-(1-pyrrolidyl)propiophenone 5 – prolintane 6 – pyrovalerone 7 – pemoline 8 – aminorex 9 – 4-methylaminorex As regards the refs., see Scarmani’s comment (but if someone is really interested in one particular compound, I suppose I could make the effort). If I had to choose one to synth, I would go with one of the morpholine derivative, purely for ease of synthesis. Hope this is of use to someone! PS - In terms of anorectic activity, compounds that inhibit re-uptake (of dopamine) are far less active than ones stimulating its release (a year of work summed up in a couple of lines - isn't science great!) That is right, the Mascara Snake: Fast and bulbous |
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scarmani (Hive Bee) 09-15-04 05:49 No 531364 ![]() |
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1-phenyl-3-azabicyclo[3.1.0]hexane (Rated as: good read) |
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> One of the results I was going to post was 1-phenyl-3-azabicyclo[3.1.0]hexane. Yes, it`s very similar to DOV 21,947. And it`s analgesic; I don`t know what kind of analgesic (narcotic or NSAID or whatever). Further information will be welcomed 1-Phenyl-3-azabicyclo[3.1.0]hexane derivatives as new ligands for sigma receptors Agostino Marrazzo, Andrea Pappalardo, Orazio Prezzavento, Franco Vittorio, and Giuseppe Ronsisvalle, Arkivoc. Vol 2004(5), 156-169 Abstract: A series of 1-phenyl-3-azabicyclo[3.1.0]hexanes were synthesized as more conformationally restricted prototypical ó ligands 3-phenylpiperidines with the aim to developing new ó ligands. Compared with 3-phenylpiperidines reported by Largent et al., binding data showed that conformational restriction was not detrimental for ó receptor affinity. Specifically, except for secondary amine 4, all racemic 1-phenyl-3-azabicyclo[3.1.0]hexane derivatives (12-19) showed moderate to high affinity for both ó1 and ó2 receptors. Dextrorotatory isomers with the same configuration of 3-phenylpiperidines to C-1 carbon linked to the phenyl ring showed a better affinity and selectivity for ó1 receptors compared to the respective levorotatory isomers. Compounds (+)-14 and (+)-15 displayed very high affinity for ó1 (Ki = 0.9 and 2.3 nM respectively) but low selectivity for receptor subtypes. Compound (+)-18 with N-phenethyl substituent embodies the highest selectivity for ó1 receptors... Sigma (ó )receptors are typical binding sites interacting with several psychoactive drugs including haloperidol, benzomorphans and phencyclidine. The ó1 subtype exhibits high affinity for (+)-benzomorphans such as (+)-pentazocine and (+)-N-allylnormetazocine (SKF-10,047) and a reduced affinity for the respective (–)-enantiomers. Based on animal model studies, this subtype seems to be involved in cocaine induced behavioral changes, in opiate induced analgesia, steroid-induced mental disturbances and alterations in immune functions. http://www.arkat-usa.org/ark/journal/200 So, it looks like N-substitution of this structure gives sigma ligands (though apparently not the unsusbtituted molecule). This might be an explanation for analgesia. Just as unrelated speculation, sigma affinity could possibly explain the odd effects of http://www.erowid.org/library/books_onli boot from the shadow of a broken mirror |
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cattleprodder (Hive Bee) 09-18-04 02:05 No 531859 |
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Help me get this straight. | Bookmark Reply | |||||
Fastandbulbous, scarmani, Rhodium or Nicodem, Is pipradol a stimulant or an analgesic? Edit: It's a stimulant. I'm not suggesting that 2-benzylpiperidine is an analgesic, and thus falls under the SAR umbrella of pipradol as Nicodem suggests, but rather a stimulant under the methamphetamine SAR domain. Then again, MDMA is both a stimulant and an analgesic, so who knows? SARs are largely conjecture and discussions of them often degenerates into different peoples' pure, theoretical and rather pointless speculation (including my own at times). In fact, computerized SAR chemistry is one of the biggest failures of modern chemistry as far as I can tell; in fact, when I was still in college they closed the new, multimillion dollar computational chemistry department because it had produced no quality research. What I'm trying to say is, all this theory is fine, but I just want to actually taste some 2-piperonylpiperidine and 2-benzylpiperidine based on my hunch, which is itself based on cut and paste chemical structure manipulation (the "me too" drug approach in the pharmaceutical world's jargon), that they will have psychoactive properties in common with Ritalin, ecstasy, meth and perhaps be even better. Until these compounds are made and synthesized and taken either by someone or at least some lab animals, then we will never really know what the acitivity is. Nicodem suggested that I search medline myself, but according to Fastandbulbous, who has apparently studied this field extensively, such a search would be futile (as he put an asterik by the 2-benzylpiperidine entry in his post, meaning that the compound is expected to have activity but does not show up in the scientific literature). However, I do agree with scarmani's statement that if 2-benzylpiperidine were especially active (say, at least as active as methamphetamine), then we would probably know of it by now, but hey, you never know. Henry Ford at one time believed that the Model T was such an advanced automobile that it could not be improved on. However, this attitude leaves no room for scientific advancement because it implies that everything in the world has already been discovered and is known. I agree that there is nothing new under the Sun and perhaps the amount of knowledge in the universe is in fact infinite, but if that is true, then more has been forgotton over the aeons than has been remembered. Also, I would like to thank scarmani for pointing out that phacetoperane hydrochloride is actually the acetate ester of 2-piperidinylphenylmethanol. However, this is only a minor problem because then all one has to do is hydrolyze off the acetate ester with a simple acid or base reflux to get the benzyl alcohol and then reduce the benzylic alcohol with either anhydrous ammonia and lithium or red phosphorous and iodine to yield 2-benzylpiperidine. Buying phacetoperane HCl from China and synthesizing 2-benzylpiperidine actually looks easier than making MDMA in many respects. From what I could tell from a quick online search, phacetoperane is not a controlled substance in the US but may be mildly controlled in Canada and Europe. The fact that 2-benzylpiperidine (and its methylenedioxy analogue) are seemingly that unexplored and that easy to make, at least in the case of the former anyway, from commercially available and OTC products makes this project very interesting to me. That is why I would very much appreciate it, Fastandbulbous, if you could dig up any information you may have or any of your research articles or other information regarding 2-benzylpiperidine or even 2-piperonylpiperidine. If someone knows how they make phacetoperane commercially I would also be grateful if they would share. I am interested in knowing the latter synthesis in hopes that it will elucidate a synthetic outline towards 2-piperonylpiperidine, which is one of my ultimate goals. Even if I don't get any more answers to these questions, this has been an excellent, informative post, you guys. Thank you for contributing so voluminously. Scarmani's post alone is almost enough to justify archiving this thread in some way, but that would be of course up to Rhodium. longimanus, I meant you would have to eat 2x as much racemic 2-benzylpiperidine, which has only one chiral center and therefore only 2 possible stereoisomers, to get the same effect as eating only x amount of the active stereoisomer of 2-benzylpiperidine. (Phacetoperane has, as you pointed out, two chiral centers and thus 4 possible stereoisomers, but I wasn't talking about eating that one.) This crude calculation, as you pointed out, is based on the assumption that one and only one of the stereoisomers retains all psychoactivity and that the other ones have none, an assumption which I am sure is not always the case but seems to be right on target in the case of methamphetamine at least. scarmani, I have tried 4-fluoroamphetamine and was not all that impressed. The florine atom, while very electronegative, is not much bigger than a hydrogen one, so one tends to get better pharmacological results with going up a size to at least a chlorine atom for all of one's designer drug needs. (For example, 2CI is stronger per gram than 2CB from what I've heard.) I have a feeling 3,4-difluoroamphetamine would be better than 4-fluoroamphetamine, but I would rather place my bet on 3,4-dichloromethamphetamine, taking an aromatic structural cue from sertraline (Zoloft), which also has a 3,4-dichlorobenzene ring. The most selective of all the SSRIs, however, is paroxetine (Paxil) and it has the coveted 3,4-methylenedioxybenzene ring system. Sesamol, the natural product chemical, is actually used to make Paxil I think. As for 3-methoxy-4-ethoxy(meth)amphetamine, which can definitely be made starting from diethylsulfate and cheap, plentiful, unwatched oil of eugenol, I say GO FOR IT! I am simplying itching for a real live bee to try this one. According to Barium, the PEA version of this compound is pleasant and mood elevating. I still can't figure out why Shulgin never tried 3,4-DMA either, but I guess he had his hands full. Finally, Nicodem, you mention 3-phenylpyrrolidine. I know you don't like or at least don't know what to do with stimulants, but do you like tobacco products, because N-methyl-2-(3-pyridinyl)pyrrolidine is none other than nicotine itself? How 'bout N-methyl-2-phenylpyrrolidine? Scarmani intimated a little while ago that these are already commercially available. Who wants to be the first crackhead to smoke some? Why did I select N-methyl-2-phenylpyrrolidine? I know that pyridine is less aromatic when compared to benzene because the lone pair of electrons on the heterocyclic nitrogen are at right angles to the conjugated pi system of the larger ring as a whole. Perhaps synthesizing nicotine with a benzene ring instead of a pyridine ring would result in a better (read, more addictive) product or perhaps it would be not fit any of the same receptors anymore without the lost nitrogen and be inactive. At any rate, I'm going to shut up for now and go smoke a good ole cigarrette and then munch on some more phendimetrazine. As Shulgin wrote somewhere in _PiHKAL_, "and visions of sugarplums danced in their heads." MURP (make us real pills) |
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Nicodem (Hive Bee) 09-18-04 12:17 No 531960 ![]() |
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Re | Bookmark Reply | |||||
Also, I would like to thank scarmani for pointing out that phacetoperane hydrochloride is actually the acetate ester of 2-piperidinylphenylmethanol. However, this is only a minor problem because then all one has to do is hydrolyze off the acetate ester with a simple acid or base reflux to get the benzyl alcohol and then reduce the benzylic alcohol with either anhydrous ammonia and lithium or red phosphorous and iodine to yield 2-benzylpiperidine. If you ever want to use the rP/I method to reduce phacetoperane than I strongly suggest you to leave that acetate ester as it is. Acetates are reduced even faster since the acetoxy group is a much faster leaving group than the hydroxy. Finally, Nicodem, you mention 3-phenylpyrrolidine. I know you don't like or at least don't know what to do with stimulants, but do you like tobacco products, because N-methyl-2-(3-pyridinyl)pyrrolidine is none other than nicotine itself? Nicotine acts at the nicotinic receptors and the pyridine nitrogen is essential in this interaction. Your reasoning makes no sense in neurochemical context. It is even much more far out than, for example, claiming MDMA is psychoactive because it resembles amphetamine. But the contribution of MDMA in dopamine/noradrenaline release is much lower than its contribution in releasing serotonin and inhibiting its uptake. And still here we talk about related neuromodulatory systems while the acetylcholine system is something completely unrelated and is actually a real neurotransmitter system (that is, not just neuromodulatory). If such reasoning would still be actual you would have people claiming that DXM is active because it resembles morphine and other opiates even if it is of the opposite stereochemistry. Yet the interaction of DXM with opiate receptors is negligible. The only thing that applies here is the key into the lock example. You have to have a key that can accommodate in the lock and certain points on the key that will turn the lock into the wanted position and open or close the door/receptor. It is also important that this key/molecule can pass all the obstacles to come into the contact with the lock/receptor site. PS: Nicotine is 3-(N-methyl-2-pyrrolidinyl)pyridine and its structure is not much related to the phenyl ring substituted 3-phenylpyrrolidines that I proposed. “The real drug-problem is that we need more and better drugs.” – J. Ott |
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