Structure-activity relationships hallucinogens

Shulgin AT Hallucinogens, in Burger s Medicinal Chemistry, 4th Edition, Part 3. Edited by Wolff ME. New York, Wiley, 1981, pp 1109-1137 Shulgin AT Psychotomimetic drugs structure-activity relationships, in Handbook of Psychopharmacology, Vol 11. Edited by Iversen LD, Iversen SD, Snyder SH. New York, Plenum, 1978, pp 243-336... 

MDMA is believed to have unique psychoactive properties that clearly distinguish it from hallucinogenic or psychostimulant phenethylamines. Not only have MDMA users consistently reported this distinctiveness, but subsequent studies of MDMA and similar compounds, in many laboratories, have shown that they do not fit within the structure-activity relationships that presently are understood to define the hallucinogenic amphetamines. 

Stimulus Properties of Hallucinogenic Phenalkylamines and Related Designer Drugs Formulation of Structure-Activity Relationships... 

Anderson, G.M. Braun, G. Braun, U. Nichols, D.E. and Shulgin, A.T. Absolute configuration and psychotomimetic activity. In Barnett, G. Trsic, M. and Willette, R., eds. Quasar Quantitative Structure Activity Relationships of Analgesics, Narcotic Antagonists, and Hallucinogens. National Institute on Drug Abuse Research Monograph 22. Rockville, MD the Institute, 1978. pp. 8-15. 

QUASAR QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS OF ANALGESICS, NARCOTIC ANTAGONISTS, AND HALLUCINOGENS. Gene Barnett, Ph.D. Milan Trsic, Ph.D. and Robert Willette, Ph.D. eds. 

Our goal in this discussion is to present the types of structural variations that have been studied in the various classes of hallucinogens and to explain how these changes affect biologic activity. Where possible, reasonable explanations for these differences are offered. Since we are just beginning to scratch the surface in our search for useful structure-activity relationships, the reader will soon note that most of the correlations are empirical, with no readily apparent biochemical or pharmacologic rationale. 

The authors are grateful for U. S. Public Health Service grants DA-01642 (R.A.G.), DA-01916, and DA-02189 (D.E.N.) from the National Institute on Drug Abuse. These have allowed us to carry out many of the reported studies and to continue probing the structure-activity relationships of hallucinogenic drugs. 

Kline, T., Benington, F., Morin, R. D., and Beaton, J. M. (1982) Structure-activity relationships in potentially hallucinogenic N,N-dialkyltryptamines substituted in the benzene moiety. J. Med. Chem., 25 908-913. 

Vogel, W. H., and Evans, B. D. (1977) Structure-activity relationships of certain hallucinogenic substances based on brain levels. Life Sci., 20 1629-1635. 

Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens... 

The neurotransmitter serotonin (21) has been implicated as playing a role in the mechanism of action of the hallucinogenic indolealkylamines however, the importance of other neurotransmitters cannot be ruled out at this time. Studies targeted specifically toward the elucidation of the mechanism of action of indolealkylamines are considered in other chapters, and this review is limited to a discussion of structure-activity relationships. 

Methoxy-N,N-dimethyltryptamine (O-methylbufotenine 59) is hallucinogenic in man at a parenteral dose of approximately 6 mg (204). Numerous animal studies have shown that 5-OMeDMT is behaviorally quite active (16,65-67,71,178,184). This compound also produced limb-flick behavior in cats (119) and the serotonin syndrome in rats (209). Glennon et al. (85) demonstrated that 5-OMeDMT serves as a discriminative stimulus in rats and have employed rats trained to discriminate 5-OMeDMT from saline to investigate the structure-activity relationships of various substituted N,N-dialkyltryptamine derivatives. The results of these studies have recently been reviewed (84). 

The most potent of the known hallucinogenic agents is LSD. It is orally active in man at doses of about 0.1 mg (0.05 to 0.25 mg). The vast majority of human studies involving LSD and its structural variants were performed in the 1950s and 1960s and have been reviewed in great detail (24,154,196,208). Therefore, some of the key structure-activity relationships are briefly highlighted here only for the sake of completeness. 

Compounds such as LSD or the beta-carbolines do not possess a primary amino group, are not rapidly metabolized in comparison to, for example, tryptamine, and enter the brain readily certain substituent groups can alter this situation. Members of the phenylalkylamine and indolealkylamine families of hallucinogens can produce similar effects in animals but may be capable of producing distinctive effects in man. As yet, there is no satisfactory and comprehensive structure-activity relationship that encompasses both major classes of compounds. This may be due in part to unique metabolic and distributional characteristics associated with the individual ring systems. 

G. Klopman and O. T. Macina, J. Theor. Biol., 113, 637 (1985). Use of the Computer Automated Structure Evaluation Program in Determining Quantitative Structure-Activity Relationships within Hallucinogenic Phenylalkylamines. 

Cheney, B.V., Duchamp, D.J., and Christoffersen, R.E., in "Quantitative Structure Activity Relationships of Analgesics, Narcotic Antagonists, and Hallucinogens", Barnett, G.,... 

Kaufman, J.J., in "QuaSAR. Quantitative Structure Activity Relationships, of Narcotic Analgesics, Narcotic Antagonists, and Hallucinogens", p. 250, NIDA Monograph No. 22, G. Barnett, M. Trsic and R.E. Willette, Eds., 1978. 

Barnett G, Trsic M, Willette RE, eds. QuaSAR Quantitative Structure Activity Relationships of Analgesics, Narcotic Antagonists, and Hallucinogens. NIDA Research Monograph 22. Rockville, MD National Institute on Drug Abuse, 1978. 

Jacob III, P. and A.T. Shulgin 1994. Structure-activity relationships of the classic hallucinogens and their analogs In Lin, G.C, andR-A, Glennon (Eds.) Hallucinogens An Update, (nida Research Monograph 146) National Institute on Drug Abuse, Rockville, md. pp. 74-91-... 

---