Differences in the effects of tachykinin NK1 receptor antagonists: neuronal versus smooth muscle tissues.
The effects of three tachykinin NK1 receptor antagonists (L-668,169, (+/-)-RP 67580, and (+/-)-CP 96.345) were examined for their ability to antagonise responses evoked by substance P O-methyl ester (a selective NK1 receptor agonist) in isolated neuronal tissue (rat superior cervical ganglia and guinea-pig locus coeruleus) and smooth muscle tissues (rat urinary bladder and guinea-pig ileum longitudinal muscle/myenteric plexus). (+/-)-RP 67580 was similarly effective in antagonising responses in both rat superior cervical ganglia and urinary bladder (estimated pKa value = 7.4 for both tissues); however, (+/-)-CP 96,345 was 50-fold less effective in antagonising responses in guinea-pig locus coeruleus than in ileum longitudinal muscle/myenteric plexus (estimated pKa values = 7.6 and 9.3 respectively). It is suggested that the differential effects of (+/-)-CP 96,345 may reflect the existence of a population of NK1 receptors within guinea-pig locus coeruleus that are less sensitive to the effects of this NK1 receptor antagonist.
Seabrook
G R
GR
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, UK.
Main
M J
MJ
Razzaque
Z
Z
Longmore
J
J
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D004594:Electrophysiology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D008125:Locus Coeruleus / Q000187:drug effects*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D009197:Myenteric Plexus / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology; D017783:Superior Cervical Ganglion / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects
D001713:Biphenyl Compounds; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; C076509:L 668169; D013373:Substance P; C033611:substance P, methyl ester-; C066892:CP 96345