Synthesis of the selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist (+)-(S)-2-chloro-5-methoxy-4-[5-(2-piperidylmethyl)-1,2,4-oxadiazol-3-y l]aniline

Abstract

In a search for novel 5-hydroxytryptamine 4 (5-HT4) agonists focusing on the linker group of benzamide derivatives, 2-chloro-5-methoxy-4-[5-(2-piperidylmethyl)-1,2,4-oxadiazol-3-yl]a niline (2) was prepared and its optical isomers were separated. The S isomer 2(S) showed high affinity for the human 5-HT4 receptor without affinity for the human 5-HT3 receptor, and potent 5-HT4 agonistic activity in longitudinal muscle myenteric plexus (LMMP) preparations of guinea pig ileum. The R isomer 2(R) showed opposite selectivity. As a result of other receptor binding studies, 2(S) (YM-53389) was shown to be a highly selective 5-HT4 agonist.