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Vol. 55, Issue 4, 778-786, April 1999
Division of Physical Biochemistry, National Institute for Medical
Research, London, UK (N.J.M.B.);
Medical Research Council Collaborative
Centre, London, UK (T.F., P.G., S.L.);
Department of Pharmacology,
Institute of Science and Technology Inc., Shinagawa-ku, Tokyo, Japan
(S.K.); and
Neuroscience Research Laboratories, Sankyo Co. Ltd.,
Shinagawa-ku, Tokyo, Japan (M.S.)
In radioligand binding studies, it has been reported that brucine,
N-chloromethyl brucine, and brucine
N-oxide increased the affinity of acetylcholine for
M1, M3, and M4 muscarinic
receptors, respectively, in a manner consistent with the predictions of
the ternary complex allosteric model. We now demonstrate an equivalent ability of these three allosteric agents to modulate the actions of
acetylcholine in functional studies in membranes and in whole cells.
The enhancing actions of brucine and brucine N-oxide on acetylcholine (ACh) potency at M1 and M4
receptors respectively have been confirmed in
guanosine-5'-O-(3-[35S]thio)triphosphate,
GTPase, cAMP, and intracellular Ca2+ mobilization
assays of function. In general, neither the basal nor the maximally
stimulated response to ACh is affected. The subtype-selective
allosteric effects of N-chloromethyl brucine on
M2 and M3 receptors were shown to be
qualitatively and quantitatively the same in
guanosine-5'-O-(3-[35S]thio)triphosphate
functional assays, in terms of both its affinity and cooperativity with
ACh, as those found in binding assays. Neutral cooperativity of
N-chloromethyl brucine with ACh on M4 receptor function was also observed, thereby demonstrating its "absolute subtype selectivity": a lack of action at any
concentration at M4 receptors and an action at
M2 and M3 receptors. The enhancing action of
N-chloromethyl brucine on neurogenically released ACh binding at M3 receptors was also detected in whole tissue
as an increased contraction of the isolated guinea pig ileum to
submaximal electrical stimulation. In conclusion, these functional
studies confirm that brucine analogs are allosteric enhancers of ACh
affinity at certain muscarinic receptor subtypes.
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