Neuroleptic Agents of the Benzocycloheptapyridoisoquinoline Series
Two members of the novel benzocycloheptapyridoisoquinoline class of neuroleptic agents, one of them being the clinically active butaclamol, have been resolved into their enantiomers. Psychopharmacological studies on the antagonism of amphetamine-induced stereotyped behavior show that activity reside...
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Published in | Molecular pharmacology Vol. 11; no. 6; p. 833 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
American Society for Pharmacology and Experimental Therapeutics
01.11.1975
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Online Access | Get full text |
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Summary: | Two members of the novel benzocycloheptapyridoisoquinoline class of neuroleptic
agents, one of them being the clinically active butaclamol, have been resolved into their
enantiomers. Psychopharmacological studies on the antagonism of amphetamine-induced stereotyped behavior show that activity
resides solely in the (+) enantiomers,
which are at least 100 times more active than the (-) enantiomers. These results, as well
as biochemical studies in vitro (published elsewhere), indicate that these compounds are
central dopamine receptor antagonists. Based on the crystal structures of butaclamol
and dexclamol, an optically active congener of butaclamol, and on the crystal structure
of the dopamine receptor agonist apomorphine, quantitative conformational analyses
were carried out on these semirigid ligands. The results reveal a striking similarity in
the distances between the nitrogen and the phenyl ring plane of the extended phenethylamine moieties of apomorphine and of
one of the conformers of butaclamol and dexclamol. This similarity suggests a mode of interaction of these ligands with a
common
primary binding site on the dopamine receptor. Important contributory interactions between other structural features of the
butaclamol and dexclamol molecules with accessory binding sites on the dopamine receptor macromolecule were identified. The
significance of the unique absolute configurations of the asymmetrical centers in dexclamol
is explained in terms of a nonenantiomeric topography of adjacent areas on the dopamine receptor macromolecule. |
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ISSN: | 0026-895X 1521-0111 |