The discovery of (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]-octan-3-amine as a novel, nonpeptide substance P antagonisst.
We describe the structure-activity relationship development of a series of quinuclidines which culminated in the first potent, selective, nonpeptide substance P (SP) antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-phenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine, 3 (CP-96,345). Compound 3 is a potent displacer of [3H]SP binding in human IM-9 cells and blocks SP-induced and capsaicin-induced plasma extravasation, as well as SP-induced salivation in the rat in vivo. This compound may both help to further our understanding of the interactions of small molecules with peptide receptors and serve to evaluate the therapeutic potential of a SP antagonist.
Lowe
J A
JA
Department of Exploratory Medicinal Chemistry, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340.
Drozda
S E
SE
Snider
R M
RM
Longo
K P
KP
Zorn
S H
SH
Morrone
J
J
Jackson
E R
ER
McLean
S
S
Bryce
D K
DK
Bordner
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D011919:Rats, Inbred Strains; D012472:Salivation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013373:Substance P / Q000037:antagonists & inhibitors*
D001713:Biphenyl Compounds; D013373:Substance P; D002211:Capsaicin; C066892:CP 96345