A selective and potent antagonist of substance P receptors on pancreatic acinar cells.
CP-96,345 [(2S, 3S) cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1- azabicyclo[2.2.2]octan-3-amine] belongs to a new class of nonpeptide antagonists of the substance P (SP) receptor. The effects of this compound on [125I]-labelled Bolton-Hunter substance P ([125I]-BH-SP) binding and cytoplasmic Ca2+ ([Ca2+]i) responses of pancreatic acinar cells have now been studied. IC50 of CP 96,345 for binding of [125I]-BH-SP and for SP-induced (3 x 10(-9) M) rise of [Ca2+]i were about 10(-9) M. CP-96,345 neither affected binding of [125I]-labelled Bolton-Hunter cholecystokinin octapeptide ([125I]-BH-CCK-8) nor the [Ca2+]i responses to CCK-8, carbamylcholine or bombesin. The CP-96,345-induced inhibition of [Ca2+]i responses to SP appeared reversible after withdrawal of the antagonist and was overcome by increasing the concentration of the agonist. CP-96,345 was consequently a specific and potent competitive antagonist for SP receptors on pancreatic acinar cells.
Sjödin
L
L
Pharmacological Division, Medical Products Agency, Uppsala, Sweden.
Gylfe
E
E
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006168:Guinea Pigs; D010179:Pancreas / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*
D001713:Biphenyl Compounds; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D013373:Substance P; D002118:Calcium; C066892:CP 96345