Selectivity and specificity of new, non-peptide, quinuclidine antagonists of substance P.
Two members of a new class of non-peptide antagonists of substance P, (+-)-cis-3-(2-methoxybenzylamino)-2-benzhydrylquinuclidine [(+/-)-CP-96,345; I] and (+-)-cis-3-(2-chlorobenzylamino)-2-benzhydrylquinuclidine [II], were tested for their ability to antagonize neurokinin-induced contractions of the rabbit cava and jugular veins (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3 system). Compound 1 is the most potent NK-1 receptor antagonist identified until now; its apparent affinity (pA2 = 9.52) is at least two log units higher than those of other NK-1 antagonists. Compound II is less active. Both compounds have been found to be almost inactive as NK-2 and NK-3 antagonists and should, therefore, be considered as selective for the NK-1 receptor. The new compounds have no direct myotropic effects and are specific for neurokinin (NK-1) receptors since they do not affect the myotropic effects of angiotensin, noradrenaline and bradykinin in the rabbit cava and jugular veins.
Rouissi
N
N
Department of Pharmacology, Medical School, University of Sherbrooke, Quebec, Canada.
Gitter
B D
BD
Waters
D C
DC
Howbert
J J
JJ
Nixon
J A
JA
Regoli
D
D
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D002460:Cell Line; D006168:Guinea Pigs; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000037:antagonists & inhibitors*
D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D000804:Angiotensin II; D013373:Substance P; D001920:Bradykinin; D009638:Norepinephrine