Nicodem,
Good to hear from you again! I apologize for misnaming nicotine. Now let's discuss drug discovery and logic and examine how we think differently about science and drug discovery and what, if anything, that means.
First of all, thank you very much for your advice not to hydrolyze the acetate ester before reducing with red phosphorous and iodine or anhydrous ammonia and lithium. It is this kind of practical advice that is invaluable to all chemists, and theoretically, the advice also makes sense based on the reaction mechanism and the fact that an acetate ion is a much better leaving group than a hydroxyl moiety.
Apparently, the total synthesis of 2-benzylpiperidine gets easier every day. A few days ago we were looking at starting from scratch with benzene, and now the whole scheme seems workable in one step from OTC and internet ordered chems (not that I'm planning anything like that because I'm not).
Second, you are right in that the 3-phenylpyrrolidine that you mention has little to do with nicotine. If nicotine did not require its pyridine ring in order to maintain its psychoactivity, then my mention of 2-phenylpyrrolidine would have possibly seemed less off the wall from your perspective, or maybe my thinking invariably seems weird when compared with yours--not necessarily a good or bad thing, mind you, just a fact to be noted.
However, now let's debate chemical theory as it relates to drug discovery. Of course, no matter how one goes about the process, each drug must be isolated and tested for desirable and undesirable side effects. However, there seem to be two main schools of thought with respect to drug discovery and science and religion too for that matter: inductive thinkers (who take small bits of information from varied sources and then extrapolate their findings to the big picture) and deductive thinkers (who are the typical rigid scientist type who is detail oriented and does not believe in making connections between and among academic disciplines). The scientific community prizes detailed, deductive, specific, specialized information and does not try to find patterns in the big picture. I, however, am an unconventional, inductive thinker and proud of it; I agree with Shulgin when he says that chemistry is an art, and I have more of an artist's temperament than that of a researcher. Not remarkably, I have had, in the past, trouble in academic and professional settings. For example, I believe in mythology, astrology, Hinduism, Christianity and science and have no qualms linking astrology to sp2 orbitals if necesssary.
Anyway, here is an example of my "cut and paste the chemical structure approach to drug discovery and understanding." I fully expect conventional thinking scientists like Nicodem to disdain this approach but it sometimes nevertheless holds true. However, this method was somewhat introduced by Shulgin in the guise of the "try it and see" approach.
It is obvious, as Nicodem has already pointed out, that DXM bears obvious but only distantly related structural resemblence to the poppy based opiates, such as codeine, morphine, hydrocodone and oxycodone. As an inductive generalist, I therefore would not be overly surprised if dextromethorphan acts on at least some of the known opiate receptors, but probably not a lot of them. Low and behold, if I recall correctly, DXM acts on the mu (or was it sigma?) opiate receptor to produce its cough suppressing and ketamine like disassociative states, although being only distantly related to the traditional opiates, DXM is not surprisingly a poor pain killer.
Another synthetic opiate, pentazocine is known to act on the mu or was it sigma? opiate receptor and also produces hallucinations at high doses, yet pentazocine is a much more effective painkiller than DXM (probably not when compared to levorphanol, however).
One point that I'm getting at is that I agree wholeheartedely with the Transformer I had as a child whose motto as printed on the toy's box said, "Molecular structure is the key to understanding." I love organic chemistry; it is the only symbolic form of reasoning that connects the tiny to the infinite and can be taylor made to physically create a novel molecule from a preconceived diagram. I feel the organic chemistry should be taught in high school. In fact, I feel sorry for people who can't read Kekule chemical drawings. However, I realize that I am the exception in the modern world of science in that I generalize and inductively reason to the point of connecting astrology to sp2 orbitals. Also, as a right brained thinker, I can't prove a lot of my ideas and I'm not good at coming up for the reasons I thought of something, but the years of being flamed have paid off, and now I'm proud to be different from the herd. I realize distinguishing between genius and idiocy can at times be difficult, but bear with me.
Tinkering with the chemical structure methodology has long been used in the pharmaceutical industry. It works something like this. One company comes up with a good drug, usually by trial and error, accident or plain good luck. Next, 20 other companies furiously tinker with the structure until they find a "me too" drug that they can then patent. This is how we end up with 30 different kinds of benzodiazepines, and that, in my opinion, is a good thing. I don't know what the first benzodiazepine to be invented was or how it was discovered, but I feel quite sure a computer did not predict jack shit about it. This is also the process that, starting with penicillin, 2nd, 3rd and 4th generation antibiotics came about. If this theory of drug discovery is applied to Shulgin's life work then _PiHKAL_ would be a compendium of "me too" drugs based on dopamine (DA), while _TiKHAL_ would be a compendium of drug information based on molecules of the "me too" type of serotonin (5-HT). DA and 5-HT are arguably the most important neurotransmitters involved with consciousness, so it is not surprising to me that tinkering with them yields interesting results.
Shulgin, however, is or at least was of the opinion that the mimickry aspect was imaginary or at least unprovable. However, after experiencing MDMA (a DA mimicker), TMA-2 (a 6-OH-DA mimicker) and TMA-6 (which has in common with DA only the 4-MeO functional group), I can verify that MDMA is the most pleasurable and the other two are marginal at best. It is on this mimickry aspect that Shulgin's views diverge from mine; this is probably why he never chose to taste 3,4-DMA, while I would predict it to be Ecstasy like. In the case of psilocin the similarity between it and 5-HT is undeniable. Another example is GHB and GABA.
For example, according to my theory, I fully believe the reason that MDMA gets you high is that it is shaped like a dopamine molecule made just lipophilic enough to cross the BB barrier and that MDA makes you more likely to hallucinate because DA is implicated in schizophrenia MDA resemembles DA more closely than does MDMA.
Years ago, when perusing my 1996 _Physician's Desk Reference_, I made an interesting observation: almost all the psychotropic drugs (at least 50 to 60%) had a phenylethylamine skeleton embedded in their structure somewhere or another. When I look at 2-benzylpiperidine, I see a cross between methamphetamine and methylphenidate (Ritalin) but longer lasting due to the body's relative inability to deaminate the drug. When I look at the symbol for 2-piperonylpiperidine, I see Ecstasy crossed again with Ritalin. When I look at morphine and then at MDxx, I see a common
3,4-dioxyphenylethylamino moiety and I realize that narcotic pain pills at times feel a lot like rolling. I also realize that methamphetamine and MDMA wake you up in a similar fashion and sharing the amphetamine scaffolding. I could go on (for example, I am willing to wager that you would be amazed at what happens when adding a 3,4-methylenedioxy unit to the phenethylamine portion of fentanyl), for the list is endless (for example, shrooms are just N,N-dimethylated serotonin with the hydroxyl group in a slightly different location), and of course my theory is not always right, but the future of drug abuse may depend on the art of mimickry more than anything else. Again, to quote Shulgin, psychopharmacology depends on a number of variables such as intuition, chemical skills and luck but not necessarily logic.
That, I think, is why I love it so. NOW WOULD SOMEBODY COOK UP SOME 2-benzylpiperidine, 2-piperonylpiperidine, 3-methoxy-4-ethoxy(meth)amphetamine and 3,4-dichloromethamphetamine. Thanks.