BuspironeIs Anxioselectivity Possible

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The question arises whether anxiolytic activity must always be accompanied by concomitant skeletal muscle relaxant and anticonvulsant activity as well as strong sedation. Can an anxioselective drug exist that will not interact significantly and additively with CNS depressant compounds, particularly alcohol? More significantly, both from a medical and sociologic viewpoint, will it be possible to treat anxiety and stress without the added complication of potent sedative effects, dependency, and abuse?

Evaluation of a series of cyclic imides as potential psychotropic agents yielded three candidates with tranquilizing action and very low sedative effects. The compound chosen for detailed pharmacologic evaluation, MJ9022-1, buspirone (BS), was marketed in 1986 as the first member of a new class of azaspirodecanediones. Early screening led to the erroneous belief that the compound might have antipsychotic properties. However, when further testing revealed that the compound had a taming effect without muscular incoordination (ataxia) in aggressive rhesus monkeys, its potential for anxiolytic activity was postulated. Clinical studies soon established the efficacy of BS to be equal to that of diazepam and clo-razepate. A comparison study of the effects of ethanol on BS and lorazepam showed that BS did not interact with alcohol. BS does not share diazepam's anticonvulsant activity nor its sedative or muscle relaxant properties. Both animal studies and human trials with "recreational" drug abusers showed BS not to be addictive or to reinforce illicit drug use. It appears that BS does not mimic any of the effects of BZDs except the antianxiety activity. If continued clinical experience bears this out, then the question remaining is: By what molecular mechanism(s) is the narrow psychotropic mechanism achieved?

The mechanism, at this writing, is far from clear. It is known that BS does not bind to BZD or GABA receptors.

BS has been shown to interact with dopamine receptors in vitro. Pharmacologically both DA agonists and antagonist properties have been demonstrated. There is also evidence that serotonin receptors (type 2) are involved as well as interaction with NE and ACh systems. Thus any overall mechanism presently proposed will likely be speculative. However, some evidence appears to zero in toward serotonin receptor antagonism, particularly the 5HT1A subtype, which likely mediated inhibitory effects in raphe neurons and pyramidal cells in the hippocampus. Affinity for BZD binding sites is very low. This fact goes a long way to explain the lack of sedation, ataxia, muscle relaxation, and the anticonvulsant properties of BS. The fact that BS, unlike diazepam, produces little or no loss of memory may be a considerable advantage in long-term anxiolytic therapy.

The metabolism of buspirone affords the inactive 5-hydroxybuspirone (OH on the 5-position of the pyrimidine ring). It is interesting that if the position is blocked, prolonged antipsychotic effects do occur. This may explain buspirone's lack of this effect. The 1-pyrimidinyl piperazine metabolite, which results from N4-dealkylation of BS, retains some activity and is being evaluated.

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