A series of novel 2-pyridylbenzimidazole derivatives was rationally designed and synthesized based on our previous studies on benzimidazole 14, a CB1 agonist used as a template for optimization. In the present series, 21 compounds displayed high affinities with K_i values in the nanomolar range. JM-39 (compound 39) was the most active of the series (K_iCB1 = 0.53 nM), while compounds 31 and 44 exhibited similar affinities to WIN 55212-2. CoMFA analysis was performed based on the biological data obtained and resulted in a statistically significant CoMFA model with high predictive value (q² = 0.710, r² = 0.998, r²_pred = 0.823).

A series of novel benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives 6a–f, 7a–f and their corresponding alcohols 8a–f were synthesized and evaluated for their affinity towards 5-HT_1A receptors. The influence of arylpiperazine moiety and benzo[b]thiophene ring substitutions on binding affinity was studied. The most promising analogue, 1-(benzo[b]thiophen-2-yl)-3-(4-(pyridin-2-yl)piperazin-1-yl)propan-1-one (7e) displayed micromolar affinity (K_i = 2.30 μM) toward 5-HT_1A sites. Docking studies shed light on the relevant electrostatic interactions which could explain the observed affinity for this compound.