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.
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.
Suzuki
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Iwaoka
K
K
Imanishi
N
N
Nagakura
Y
Y
Miyata
K
K
Nakahara
H
H
Ohta
M
M
Mase
T
T
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D006801:Humans; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects*; D044422:Receptors, Serotonin, 5-HT4; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism