New 5-hydroxytryptamine1A receptor ligands containing a norbornene nucleus:: Synthesis and in vitro pharmacological evaluation

New arylpiperazine derivatives were prepared to identify highly selective and potent ligands for the 5-hydroxytryptamine 1A (5-HT1A) receptor as potential pharmacological tools in studies of central nervous system (CNS) disorders. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain, and arylpiperazine) known to introduce 5-HT1A receptor affinity and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in the nanomolar and sub-nanomolar ranges at 5-HT1A and moderate to no affinity for other relevant receptors (5-HT2A, 5-HT2C, D-1, D-2, alpha(1), and alpha(2)). The 4-[3-[4-(o-methoxyphenyl)piperazin-1-yl]propoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (3b), with K-i = 0.021 nM, was the most active and selective derivative for the 5-HT1A receptor with respect to other serotonin receptors, whereas the most selective derivative for dopaminergic and adrenergic receptors was a CF3-substituted arylpiperazine (2e). As a general trend, compounds with a piperazinylpropoxy chain (3b-g) showed a preferential affinity for the 5-HT1A receptor, suggesting that the alkyl chain length represents a critical structural feature in determining 5-HT1A receptor affinity and selectivity, as confirmed by the molecular modeling invoked for explaining the differential binding affinities of the new arylpiperazines.