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.

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Exposure of rat C6 glioma cells to either agonists or agents that increase cyclic AMP levels leads to down-regulation of 8,-adrenergic receptors (01AR) as measured by loss of radioligand binding sites . The present study examines the influence of isoproterenol and forskolin treatment on levels of,6 1AR mRNA, mRNA stability, and gene transcription rate . Isoproterenol treatment of C6 cells altered,6 1AR mRNA levels in a biphasic manner ; i .e ., short-term exposure (30-60 min) increased by 50%, whereas longer exposure (2-6 h) decreased by 50% the levels of ,61 AR mRNA . The extent of both the up-and down-regulation was dependent on agonist concentration . Similar regulation of 6 1AR mRNA was observed in forskolin-treated cells . Pretreatment of the cells with Pseudomonas exotoxin A, a potent inhibitor of protein synthesis, completely blocked isoproterenol-and forskolin-mediated down-regulation of ,6 1AR mRNA, and

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