Hallucinogens phenylethylamines

Low doses of both indole and phenylethylamine hallucinogens potentiate the normal neophobia exhibited by rats placed into a novel environment, which typically results in an initial suppression of locomotion and investigation. These effects are extremely susceptible to the influences of ambient stimulation and handling. The action of hallucinogens on inhibitory 5-HT autoreceptors does not appear to be responsible for these effects. The relevance of either inhibitory or excitatory 5-HT receptors on target neurons to these effects of hallucinogens should be more thoroughly examined. 

Chemical Structures. Figure 1 shows the chemical structures for 14 phenylethylamine compounds. Nine of these compounds are used clinically as anorectics (ii-amphetamine, phentermine, diethylpropion, phenmetrazine, phendimetrazine, clotermine, chlorphentermine, benzphetamine, and fenfluramine). Four of these compounds are not approved for clinical use and are reported to have hallucinogenic properties (MDA, PMA, DOM, and DOET). The final compound ( /-ephedrine) is used clinically for bronchial muscle relaxation, cardiovascular, and mydriatic effects. Figure 2 shows the chemical structure for MDMA, the methyl analog of MDA. MDMA is not approved for clinical use and has been reported to produce both LSD-like and cocaine-like effects. 

The stimulation of locomotor activity by MDMA and the importance of mesolimbic dopamine in this response reflect similarities with the prototype phenylethylamine stimulant, amphetamine. It is important to note that these parameters are frequently associated with rewarding aspects of drugs and drug abuse. Additionally, the behavioral profiles of MDMA and I E share certain characteristics with hallucinogen-Iike agents. This unique mixture of stimulus properties and neurochemical actions may contribute to a dangerous behavioral toxicity and neurotoxic potential for drugs like MDMA. 

While the majority of studies have focused on LSD, some evidence suggests that hallucinogens derived from the phenylethylamine nucleus affect locomotion in a manner that is interpretable only by considering the environmental context. For example, the substituted amphetamine DOM produces a dose-dependent (0.5-10 mg/kg) reduction in locomotor activity when rats are tested in a novel open field, while a slight but significant increase in activity is observed in a familiar environment (171). This report corroborates the separate findings of DOM-induced hyperactivity in rats or mice in a familiar chamber (29,196) and hypoactivity in mice in an unfamiliar setting (92). Mescaline (10 mg/kg) has also been reported to increase locomotion in rats in a familiar environment (196). 

N-methylation of hallucinogenic amphetamines seems to produce a very smooth, mellow, euphoric trip, and the same is probably true for phenylethylamines. 

The hallucinogens generally fall into two chemical classes. The indole alkylamines include LSD, psilocybin, psilocin, dimethyltryptamine (DMT), and diethyltrypta-mine (DET), all of which are structurally similar to serotonin. The other chemical subclass of hallucinogens contains phenylethylamine derivatives such as mescaline, MDMA, MDA, and DOM (dimethoxymethyl amphetamine). A related stimulatory hallucinogen, PCP, is a piperidine analogue that produces unique effects. 

LSD (a hallucinogen) and codeine (a narcotic) are structurally more complex derivatives of 2-phenylethylamine. Identify the atoms of 2-phenylethylamine in each of the following compounds. 

Aromatic amino acids that originate from the shikimate pathway also act as precursors to many alkaloids. Alkaloids that contain a phenylethylamine moiety are derived from L-tyrosine or its oxidation product L-dihydroxyphenylalanine (L-DOPA). Mescaline (N7) originating from the latter amino acid is known to occur in several cacti and is responsible for the hallucinogenic activity of peyote (Lophophora williamsii, Cactaceae). Lophocerine is a tetrahydroisoquinoline alkaloid derived from L-dopamine and found to occur in a different Lophophora species, L. schotti. 

MMDA (methoxymethylenedioxyamphetamine) is a phenylethylamine compound structurally related to amphetamine and mescaline. It is a potent psychotropic (hallucinogenic) but is not used in therapeutics. It is a drug of abuse. 

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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