Characterization of the interaction of the cervane alkaloid, imperialine, at muscarinic receptors in vitro.
The action of the cervane alkaloid, imperialine, has been assessed at M1, M2 and M3 receptors in functional assays and at M1, M2, M3 and putative M4 sites in binding studies. In functional studies, imperialine acted as a selective surmountable antagonist at M2 receptors in guinea-pig isolated atria and uterus (-log KB = 7.7 and 7.4, respectively), in comparison to M1 receptors in canine isolated saphenous vein (-log KB = 6.9) or M3 receptors in a range of guinea-pig isolated smooth muscles including ileum, trachea, fundus, seminal vesicle or oesophagus (-log KB = 6.6-6.8). In rat aorta, the -log KB value at the M3 receptor (5.9) was slightly, but significantly, lower. In competition radioligand binding studies, imperialine was also selective toward to M2 sites in rat myocardium (-log Ki = 7.2) with respect to M1 and M3 sites (rat cerebral cortex, rat submaxillary gland; -log Ki = 6.1 and 5.7, respectively). However, it did not significantly discriminate between rat cardiac M2 sites and putative M4 sites in rabbit lung (-log Ki = 6.9). Imperialine resembles the alkaloid himbacine in terms of its pharmacological profile at muscarinic receptor subtypes in that it acts as an M2 selective antagonist with respect to M1 or M3 sites. It may also provide a second, commercially available, antagonist with which to discriminate between M1 and M4 receptors.
Eglen
R M
RM
Institute of Pharmacology, Syntex Research, Palo Alto, CA 94304.
Harris
G C
GC
Cox
H
H
Sullivan
A O
AO
Stefanich
E
E
Whiting
R L
RL
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002595:Cevanes / Q000494:pharmacology*; D004148:Dioxolanes / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005748:Gastric Fundus / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008297:Male; D018727:Muscarinic Antagonists; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010946:Plants, Medicinal; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000502:physiology; D012669:Seminal Vesicles / Q000187:drug effects / Q000502:physiology
D000470:Alkaloids; D002595:Cevanes; D004148:Dioxolanes; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; C047331:peiminine