Thiophene systems. 12. Analogues of ketanserin and ritanserin as selective 5-HT2 antagonists

Abstract A series of thieno[3,2- d ]-, [3,4- d ]- and [2,3- d ]pyrimidinedione derivatives was prepared with N -3 substitution containing the side chains of ketanserin and ritanserin. The best of these thiophene analogues were the isosteres of ketanserin which were up to 20-fold more potent than the standards in 5-HT 2 binding assays. More importantly, in addition to their increased potency, these derivatives were more selective than the standards in that they had less affinity for 5-HT 1A and α 1 binding sites. This selectivity is especially noted as the ratio of α 1 5-HT 2 wherein the most interesting thiophene isostere ( 2 ) in this study had a binding selectivity > 12-fold of ketanserin or ritanserin.