Synthesis and in vitro pharmacological evaluation of a new series of 5-HT1A 5-HT2A and 5-HT2C receptor ligands containing a norbornene nucleus.

A series of 4-substituted piperazine derivs. bearing a norbornene nucleus have been prepd. and their affinity for serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors has been evaluated. Compds. showing the highest affinity have been selected and evaluated on dopaminergic (D1 and D2) and adrenergic (.alpha.1 and .alpha.2) receptors. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain and 4-substituted piperazine) known to be crit. in order to have affinity on serotonin receptors and the proper selection of substituents led to compds. with higher receptor specificity and affinity. In binding studies, several mols. showed affinity in nanomolar range towards 5-HT1A 5-HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1, D2, .alpha.1 and .alpha.2). Compd. 2q 4-[2-[4-(3,4-dichlorophenyl)piperazin-1 -yl]ethoxy]-4-aza-tricyclo[5.2. 1 .02,6]dec-8-ene-3,5- dione (Ki = 1.13 nM), was the most active and selective deriv. for the 5-HT2C receptor with respect to other serotonin, dopaminergic and adrenergic receptors. Moreover, compd. 3p showed mixed 5-HT2A/5-HT2C activity with affinity values in nanomolar range.