S-14489

In the present study, using a two-lever drug discrimination procedure, we characterized the effects of a series of chemically-diverse, novel 5-HT1A receptor agonists and antagonists in rats trained to discriminate the serotonin (5-HT)1A receptor agonist, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) (0.31 mg/kg, i.p.) from saline. In analogy to the 5-HT1A receptor agonists, ipsapirone (a pyrimidinylpiperazine) and flesinoxan (a benzodioxane), the arylpiperazine derivatives, WY-48,723 and WY-50,324, as well as the methoxynaphtylpiperazines, S 14506 and S 14671, substituted 100% for the discriminative stimulus (DS) effects of 8-OH-DPAT, with the latter two displaying remarkable potency [50 effective doses (ED50s): 1.25, 0.34, 0.05, 0.69, 0.009 and 0.006 mg/kg, s.c., respectively]. In contrast, an additional pyrimidinylpiperazine, zalospirone, failed to fully mimick the training drug (maximal effect: 40%) even at a dose markedly disrupting response rates (2.5 mg/kg, s.c.). The potency of agonists in generalizing to 8-OH-DPAT correlated significantly (P < .05) with their affinity at rat hippocampal 5-HT1A receptors in vitro (r = .78), and with their potency to induce hypothermia in the rat (r = .96). S 15535 and S 15931, novel benzodioxopiperazines possessing mixed 5-HT1A autoreceptor agonist/postsynaptic 5-HT1A receptor antagonist properties, antagonized (approximately 75%) the discriminative stimulus (DS) properties of 8-OH-DPAT (ED50s: 6.9 and 0.97 mg/kg, s.c., respectively), although their structural analogue, S 14489, reduced by only 50% the action of 8-OH-DPAT. The 5-HT1A receptor antagonists, (+/-)-pindolol (-70%; ED50: 0.65 mg/kg, s.c.), (-)-alprenolol (-67%; ED50: 7.1) and NAN-190 (-80%; ED50: 1.5), all blocked the 8-OH-DPAT DS. Likewise, several novel antagonists at 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors; the benzoisothiazolpiperazine, SDZ 216-525 (-83%; ED50: 0.64), the aryloxyalkylamine, (-)-tertatolol (-83%; ED50: 7.7) and the methoxyphenylpiperazine, (+)-WAY 100,135 (-80%; ED50: 17.0), antagonized the 8-OH-DPAT cue. Antagonist potency correlated significantly with affinity at 5-HT1A receptors (r = .83) and potency for antagonism of 8-OH-DPAT-induced hypothermia (r = .83). Antagonists showed only variable and not significant (P > .05) generalization rates (13-50%) when tested alone.(ABSTRACT TRUNCATED AT 400 WORDS)

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-HT1A 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-HT1A receptors versus alpha 1-, alpha 2-, and beta-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-HT1A sites (8.10 < or = pKis < or = 9.35), and the majority behaved as antagonists in vivo in blocking the hypothermia induced by the 5-HT1A 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 for 5-HT1A 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-HT1A versus alpha 1-adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pKi = 8.75), marked antagonist activity, and selectivity toward alpha 1-adrenergic (81-fold) and dopamine D2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT1A 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-HT1A receptors.