Characterization of potent and selective antagonists at postsynaptic 5- HT(1A) receptors in a series of N4-substituted arylpiperazines

Article abstract of DOI:10.1021/jm00020a020

Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT(1A) receptors. From the numerous arylpiperazines described in the literature, 1- (2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT(1A) receptors versus α₁- , α₂-, and β-adrenergic receptors, as well as dopamine D₁ and D₂ receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin- 6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. All compounds showed high affinity at 5-HT(1A) sites (8.10 ≤ pK(i)s ≤ 9.35), and the majority behaved as antagonists in viva in blocking the hypothermia induced by the 5-HT(1A) agonist 8-OH-DPAT in the absence of a marked effect alone at equivalent doses. An in vivo evaluation of dopamine D₂ receptor antagonist properties revealed that the majority of compounds was devoid of activity at this site, in marked contrast to BMY 7378 which displayed virtually no selectivity far 5-HT(1A) versus dopamine D₂ receptors. Moreover, six compounds of the present series, 8, 10, 11, 14, 25, and, 37, showed > 10-fold selectivity in vitro for 5-HT(1A) versus α₁- adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pK(i) = 8.75), marked antagonist activity, and selectivity toward α₁-adrenergic (81-fold) and dopamine D₂ (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT(1A) antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT(1A) receptors.