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Vol. 58, Issue 1, 194-207, July 2000
MRC Technology (S.L., A.P.), Mill Hill, London; and Division of
Physical Biochemistry, National Institute for Medical Research, Mill
Hill, London, United Kingdom (N.J.M.B.)
We have studied the interactions of five indolocarbazoles with
N-[methyl-3H]scopolamine (NMS) and
unlabeled acetylcholine at M1-M4 muscarinic receptors, using equilibrium and nonequilibrium radioligand binding studies. The results are consistent with an allosteric model in which
the primary and allosteric ligands bind simultaneously to the receptor
and modify each other's affinities. The compounds were generally most
active at M1 receptors. [3H]NMS binding was
enhanced by staurosporine, KT5720, and KT5823 at M1 and
M2 receptors, and by K-252a at M1 receptors.
Gö 7874 reduced [3H]NMS affinity by up to threefold for
all subtypes. A range of cooperative effects with acetylcholine was
seen, and, at the M1 receptor, KT5720 had a log affinity of
6.4 and enhanced acetylcholine affinity by 40%. The compounds
inhibited the dissociation of [3H]NMS to different
extents across the receptor subtypes, with the largest effects at
M1 receptors. In equilibrium binding studies the inhibitory
potency of gallamine at M1 receptors was not affected by
KT5720, indicating that these agents bind to two distinct allosteric sites and have neutral cooperativity with each other. In contrast, gallamine and staurosporine had a negatively cooperative or competitive interaction at M1 receptors. Similarly, the potency and
relative effectiveness of KT5720 for inhibiting [3H]NMS
dissociation from M1 receptors were not affected by
gallamine or brucine, but were affected in a complex manner by
staurosporine. These results demonstrate that there are at least two
distinct allosteric sites on the M1 receptor, both of which
can support positive cooperativity with acetylcholine.
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