Phenylalkylamine hallucinogens

The phenylalkylamine hallucinogens show a close structural resemblance to the catecholamines, noradrenahne and dopamine. The prototype structure is found in mescaline, a naturally occurring substance. Modification of the mescaline molecule has led to synthetic amphetamine derivatives with hallucinogenic action. 

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Mg/kg LSD is given at 3 hourly intervals with the animals being tested only after the last injection (32). Cross tolerance has been observed to other indole and phenylalkylamine hallucinogens (11). Similar effects were also reported for other hallucinogens (10) with an order of potency that paralleled that seen in humans (2) that is, the (hallucinogenic) -isomer of LSD was about 10 times as potent as psilocybin and 100 times as potent as mescaline (10). 

Clare, B.W. (2002) QSAR of benzene derivatives comparison of classical descriptors, quantum theoretic parameters and flip regression, exemplified by phenylalkylamine hallucinogens. 

Clare, B.W. (1998). The Frontier Orbital Phase Angles Novel QSAR Descriptors for Benzene Derivatives, Applied to Phenylalkylamine Hallucinogens. J. Med. Chem. 41, 3845 -3856. 

History, Prevalence of Abuse, and Pharmacology of Hallucinogenic Phenylalkylamine Derivatives... 

The natural prototype for the phenylalkylamines is mescaline (Structure 1), isolated from the peyote cactus (Lophophora williamsii) by Heffter in 1896 (100) and subsequently obtained synthetically by Spath in 1919 (218). Used for many centuries in the form of peyote by Indians in Mexico and the American Southwest (3), it is often referred to as one of the classic hallucinogens, along with psilocybin, psilocin, and LSD. Little structure-activity work was directed toward mescaline or its congeners until 1955, when Peretz et al. (174) reported that a-methyl mescaline (TMA) (8), which represented a hybrid of the structure... 

For the purposes of this chapter, hallucinogens are divided into two separate categories. The first section covers the substituted phenylalkylamines, with the prototype for these structures being mescaline. The second category includes indole-based compounds, including various substituted tryptamines, beta-car-bolines, and LSD. 

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. 

Akihiko Himeno, Dennis J. McKenna, Adil J. Nazarali, and Juan M. Saavedra. "(+ )DOI, a hallucinogenic phenylalkylamine, downregulates 5HT2 receptors in rat brain." Neuroscience Abstracts 14 (1988), no. 229.2. 

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. 

Phenylalkylamines, the phenylethylamines and the phenylisopropylamines, represent the largest group of classical hallucinogens (29,30). The phenylethylamines are the a-desmethyl counterparts of the phenylisopropylamines as with the indolealkylamines, the presence of the a-methyl group increases ... 

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