Ej. Homan et al., Synthesis and pharmacology of the enantiomers of the potential atypical antipsychotic agents 5-OMe-BPAT and 5-OMe-(2,6-di-OMe)-BPAT, BIO MED CH, 7(7), 1999, pp. 1263-1271
The optically pure enantiomers of the potential atypical antipsychotic agen
ts 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (5-OMe-BPAT,
5) and 5-methoxy-2-{N-[2-(2,6-dimethoxy)benzamidoethyl]-N-n-propylamino}tet
ralin [5-OMe-(2,6-di-OMe)-BPAT, 6] were synthesized and evaluated for their
in vitro binding affinities at alpha(1)-, alpha(2)-, and beta-adrenergic,
muscarinic, dopamine D-1, D-2A,D- and D-3, and serotonin 5-HT1A and 5-HT2 r
eceptors. In addition, their intrinsic efficacies at serotonin 5-HT1A recep
tors were established in vitro. (S)- and (R)-5 had high affinities for dopa
mine D2A, D3, and serotonin 5-HT1A receptors: moderate affinities for alpha
(1)-adrenergic and serotonin 5-HT2 receptors, and no affinity (K-i > 1000 n
M) for the other receptor subtypes. (S)- and (R)-6 had lower affinities for
the dopamine D-2A and the serotonin 5-HT1A receptor, compared to (S)- and
(R)-5, and hence showed some selectivity for the dopamine D3 receptor. The
interactions with the receptors were stereospecific, since the serotonin 5-
HT1A receptor preferred the (S)-enantiomers, while the dopamine D-2A and D-
2 receptors preferred the (R)-enantiomers of 5 and 6. The intrinsic efficac
ies at the serotonin 5-HT1A receptor were established by measuring their ab
ility to inhibit VIP-induced cAMP production in GH(4)ZD10 cells expressing
serotonin 5-HT1A receptors. Both enantiomers of 5 behaved as full serotonin
5-HT1A receptor agonists in this assay, while both enantiomers of 6 behave
d as weak partial agonists. The potential antipsychotic properties of (S)-
and (R)-5 were evaluated by establishing their ability to inhibit d-ampheta
mine-induced locomotor activity in rats, while their propensity to induce e
xtrapyramidal side-effects (EPS) in man was evaluated by determining their
ability to induce catalepsy in rats. Whereas (R)-5 was capable of blocking
d-amphetamine-induced locomotor activity, indicative of dopamine D-2 recept
or antagonism, (S)-5 even enhanced the effect of d-amphetamine, suggesting
that this compound has dopamine D-2 receptor-stimulating properties. Since
both enantiomers also were devoid of cataleptogenic activity, they are inte
resting candidates for further exploring the dopamine D-2/serotonin 5-HT1A
hypothesis of atypical antipsychotic drug action. (C) 1999 Elsevier Science
Ltd. All rights reserved.