Identification of a novel 4-aminomethylpiperidine class of M3 muscarinic receptor antagonists and structural insight into their M3 selectivity.
Identification of a novel class of potent and highly selective M(3) muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M(3) selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M(3) antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M(3) selective antagonist that had >100-fold selectivity versus the M(1), M(2), M(4), and M(5) receptors (M(3): K(i) = 0.30 nM, M(1)/M(3) = 570-fold, M(2)/M(3) = 1600-fold, M(4)/M(3) = 140-fold, M(5)/M(3) = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M(3) antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M(3) receptors.
Sagara
Yufu
Y
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. yufu_sagara@merck.com
Sagara
Takeshi
T
Uchiyama
Minaho
M
Otsuki
Sachie
S
Kimura
Toshifumi
T
Fujikawa
Toru
T
Noguchi
Kazuhito
K
Ohtake
Norikazu
N
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014320:Triphenylmethyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C514168:1-(4-hydroxy-1-(3,3,3-tris(4-fluorophenyl)propanoyl)pyrrolidine-2-yl)carbonyl-N-(4-piperidinylmethyl)pyrrolidine-2-carboxamide; D004151:Dipeptides; D010880:Piperidines; D043587:Receptor, Muscarinic M3; D014320:Triphenylmethyl Compounds