1-(2-Methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190; 1a) is a putative postsynaptic 5-HT1A serotonin antagonist. This high affinity ligand (Ki = 0.6 nM), although selective for 5-HT1A versus other 5-HT receptors, binds with nearly equal affinity at alpha 1-adrenergic receptors (Ki = 0.8 nm). Structure-affinity relationship studies were conducted in order to achieve an improved selectivity. Replacement of the phthalimide moiety by substituted benzamides led to retention of 5-HT1A affinity but to no improvement in selectivity, whereas replacement by alkyl amides proved beneficial, leading to an improvement in affinity and selectivity. Branching alpha to the amide carbonyl group and increased bulkiness of the alkyl moiety further improved 5-HT1A affinity and selectivity. 4-[4-(1-Adamantanecarboxamido)butyl]-1- (2-methoxyphenyl)piperazine (2j) was found to bind at 5-HT1A sites with high affinity (Ki = 0.4 nM) and with a 160-fold selectivity over alpha 1-adrenergic sites. Preliminary studies show that this agent retains antagonist activity as determined in a 5-HT1A-coupled adenylyl cyclase assay. Further functional studies are warranted to fully characterize this agent.

The effects of different acute stressors on circulating corticosterone levels, 5-HT _1A receptors and 5-HT_1A mRNA levels were measured in male Sprague-Dawley rats. Two hours restraint stress, short swim stress (15 min) and long swim stress (30 min) increased circulating corticosterone levels 10-, 13- and 18-fold, respectively, when measured immediately after termination of the stress. Each stressor produced a unique profile of changes in 5-HT_1A receptors measured in coronal sections 24 h after the termination of stress with the antagonist [¹²⁵I]-4-(2’-methoxyphenyl)-1-[2’-(n-2’’-pyridinyl)-p-iodobenzamido]ethylpiperazine and the agonist [³H]-8-hydroxy-2-(di-n-propylamino)tetralin. Restraint stress produced decreases in antagonist binding in the CA3 region and dentate gyms; agonist binding was decreased only in the dentate gyms. Despite the larger elevation in circulating corticosterone level measured after short swim stress, no changes in agonist or antagonist binding were detected after this stressor. In contrast, the long swim stress increased antagonist binding in the CA2 region and in layers IV–VI of the cortex; agonist binding was also increased in all regions of the hippocampus and in layers I–VI of the cortex. Thus, restraint and long swim stress produce opposite effects on 5-HT _1A receptor expression in different subregions of the hippocampus. Analysis of presynaptic 5-HT_1A receptors in the raphe nuclei revealed an increase in antagonist binding in the dorsal raphe following long swim stress. No change in the level of 5-HT_1A mRNA measured in adjacent sections was detected following any of the stressors. The role of corticosteroid receptors in these stress-induced alterations of 5-HT_1A receptors and the potential significance of these alterations in the context of affective disorders are discussed.

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The subject compounds were prepared as a part of a continuing structure-activity study of the contrasting actions (agonism-antagonism) of (+)- and (-)-11-hydroxy-10-methylaporphine at serotonin (5-HT1A) receptors. None of the targeted nonoxygenated aporphine derivatives demonstrated significant activity in assays for any effects at serotonin 5-HT1A receptors. It is concluded that, in the aporphine series, serotonergic agonist or antagonism requires an alkyl group ortho to a phenolic OH group in the A ring.