new scaffold for D[3] dopaminergic affinity containing arylpiperazine - fragment: molecular modeling, synthesis, in vitro and in vivo pharmacological evaluation

ABSTRACT

A new series of N-[6-substitutedbenzo[d]thiazol-2-yl]-2-[4-arylpiperazin-1-yl] acetamides [3a-f] and 2-[3-[4-arylpiprazin-l-yl]propylthio]benzo[d]thiazoles/-oxazoles/-imidazole [6a-f] was synthesized by connecting arylpiperazine through a semi-rigid or flexible spacer to a heterocyclic moiety, respectively. The radioligand binding experiments for the D[1], D[2], D[3] and D[5] subtypes expressed in CHO cells were examined for the target compounds 3a-f, 6a, 6b, 6d and 6f, Compound 6a showed the best binding affinity for dopamine D[3] receptor and is considered as a new scaffold for D[3] dopaminergic affinity. Furthermore, molecular modeling of the best-fitted conformer of target compounds 3a, 6b, 6c, 6d and 6f to alph[1]-adrenoceptor [alph [1]-AR] antagonist hypothesis was performed, using CATALYST software, HipHop modules. Based on the results of simulation studies, these target compounds were evaluated for their in vivo hypotensive activity on blood pressure of normotensive cats