(+)-Lysergic Acid Diethylamide
Both an indolethylamine group and a phenylethylamine group can be seen in the structure of the extraordinarily potent hallucinogen LSD. The stereochemistry is exceedingly important. Chirality, as shown, must be maintained or activity is lost; likewise, the location of the double bond, as shown, is required.37 Experimentally, LSD has marked effects on serotoninergic and dopaminergic neurons. The bases for all of its complex CNS actions are not completely understood, however. Recently, its actions have been suggested as being more typical of schizophrenic psychotic reactions than the model based on amphetamine. For more on this, see the discussion of atypical antipsychotics (Chapter 12).
Phencyclidine was introduced as a dissociative anesthetic for animals. Its close structural relative ketamine is still so used and may be used in humans (Chapter 22). In humans, PCP produces a sense of intoxication, hallucinogenic experiences not unlike those produced by the anticholinergic hallucinogens, and often, amnesia.
with added steric bulk may suffice for this action. An interaction between a hydrogen atom on the nitrogen of the proton-ated form of cocaine and an oxygen of the benzoyl ester group, or alternatively, an interaction between the unshared electron pair of the freebase nitrogen and the carbonyl of the benzoyl ester group, could approximate this moiety.
Considerable research on drugs affecting the DAT has been published in recent years. A review of pharmacothera-peutic agents for cocaine abuse is available.41
There are two conventions for numbering THC: that arising from terpenoid chemistry produces A1-THC and that based on the dibenzopyran system results in a A9-THC designation. The terpenoid convention is used here.
The drug affects many systems, including those of NE, DA, and 5-HT. It has been proposed that PCP (and certain other psychotomimetics) produces a unique pattern of activation of ventral tegumental area dopaminergic neurons.38 It blocks glutaminergic n-methyl-d-aspartate receptors.39 This action is the basis for many of its CNS effects. PCP itself appears to be the active agent. The psychotic state produced by this drug is also cited as a better model than amphetamine psychosis for the psychotic state of schizophrenia.40
Cocaine as a euphoriant-stimulant, psychotomimetic, and drug of abuse could as well be discussed with amphetamine and methamphetamine, with which it shares many biological properties. At low doses, it produces feelings of well-being, decreased fatigue, and increased alertness. Cocaine tends to produce compulsive drug-seeking behavior, and a full-blown toxic psychosis may emerge. Many of these effects appear to be related to the effects of increased availability of DA for interaction with postsynaptic receptors (D2 and D3 receptors are pertinent). Cocaine is a potent DA reuptake blocker, acting by competitive inhibition of the DAT. A phenethylamine moiety
Tetrahydrocannabinoid is a depressant with apparent stimulant sensations arising from depression of higher centers. Many effects, reputedly subjectively construed as pleasant, are evident at low doses. The interested reader may consult a pharmacology text for a detailed account. At higher doses, psychotomimetic actions, including dysphoria, hallucinations, and paranoia, can be marked. Structural features associated with activity among cannabis-derived compounds have been reviewed.42 Notably, the phenolic OH is required for activity. Certain SARs (especially separation of potency between enantiomers) for cannabinoids suggested action at receptors.43 Two receptors for THC have been discovered. The relevant receptor for CNS actions is CB1.44 CB2 occurs in immune tissues. The first natural ligand found for the receptor is the amide derivative of arachidonic acid, anandamide.45 Other natural cannabinoids are arachidonic acid 2-glycerol ester and 2-arachidonyl glycerol ether.46 The endogenous cannabinoid system appears to function as a retrograde messenger system at both stimulatory synapses and depressant synapses. The synaptic transmitter causes postsynaptic syntheses of endocannabinoids that are then transported to CB1 receptors located presynaptically where they fine-tune both excitatory and inhibitory neurons.47-51 Because CB1 receptors appear to be present in all brain areas and affect both excitatory and inhibitory systems, the prospect of developing selective cannabinoid drugs acting at receptors is considered not good. Designing drugs to affect the transporter is considered the most promising research route.
Endocannabinoids, as regulated by leptin, are also involved in maintaining food intake and in other behaviors.52,53
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