[1]Benzothieno[3,2-d]pyrimidine derivatives as ligands for the serotonergic 5-HT₇ receptor

The present paper describes the synthesis and the binding properties for the serotonergic 5-HT₇ and 5-HT_1A receptors of three new series (A-C) of (benzo)thienopyrimidinone derivatives. All series exhibit a basic moiety at the 2-position of the heterocyclic scaffold such as N,N-dialkylaminoalkylthio chain in series A and phenylpiperazine, benzylpiperazine, or benzylpiperidine alkyl chain in series B and C. Compounds endowed with the best binding properties at 5-HT₇R belong to the B and C types. In particular, derivatives B2 and C1 (RSC4) exhibit notable affinity for 5-HT₇R (K_i = 9.08 and 0.85 nM, respectively) and selectivity over the 5-HT_1AR (254- and 48-fold, respectively). The structure-affinity relationships for these three new classes of 5-HT₇R ligands are discussed and, in order to rationalize and deeply investigate the observed results, molecular modeling studies were performed. In particular, the binding poses of the synthesized compounds were studied by docking them in the two receptor proteins suitably built by homology modeling. The calculated binding energies resulted in an excellent agreement with the experimental measured K_i, further validating the quality of the models.