SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A NEW MODEL OF ARYLPIPERAZINES .1. YL]METHYL]-1,3-DIOXOPERHYDROIMIDAZO[1,5-A]PYRIDINE - ASELECTIVE 5-HT1A RECEPTOR AGONIST

A series of new bicyclohydantoin-arylpiperazines was prepared and eval uated for affinity at 5-HT1A, alpha(1), and D-2 receptors. Most of the compounds showed very low affinity for D-2 receptors, and most of the m demonstrated moderate to high affinity for 5-HT1A and alpha(1) recep tor binding sites. SAR observations indicated that the length of the a lkyl chain between the arylpiperazine and the hydantoin moiety is of g reat importance for 5-HT1A/alpha(1) affinity and selectivity, n = 1 be ing the optimal value. Compound 1h, l]methyl]-1,3-dioxoperhydroimidazo [1,5-a]pyridine, bound at 5-HT1A sites with nanomolar affinity (K-i = 31.7 nM) and high selectivity over alpha(1), D-2, and 5-HT2A receptors (K-i > 1000, > 10 000, and > 1000 nM, respectively). Preliminary stud ies showed that this agent is probably functioning as a partial to ful l 5-HT1A agonist, and it displayed anxiolytic activity on the social i nteraction test in mice.