SAR at alpha1-adrenoceptor subtypes and 5-HT1A receptors within a novel series of 1,3-Dioxolane-based ligands.

Receptors for adrenaline/noradrenaline and serotonine (5-HT) are an heterogeneous population, ubiquitously distributed in the whole organism. These receptors belong to the G-protein-coupled receptor (GPCR) superfamily which represent the molecular target for over 45% of all marked drugs. We have recently reported on a new series of 1 adrenergic antagonists bearing a 1,3-dioxolane structure among which compounds A is outstanding in terms of affinity and selectivity [1]. Binding studies have demonstrated that these molecules bind also with good affinity at 5-HT1A receptors. In order to improve activity and selectivity we have studied the effect of the introduction of lactame and imide moieties as depicted below. The results of the functional and binding studies at 1-adrenoceptor subtypes as well as the binding studies at human cloned 5-HT1A receptors will be discussed during the congress.