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Vol. 62, Issue 6, 1492-1505, December 2002
Medical Research Council Technology, Mill Hill, London, UK (S.L.,
A.P.) and Division of Physical Biochemistry, National Institute for
Medical Research, Mill Hill, London UK (N.J.M.B.)
WIN 51,708 (17-
-hydroxy-17-
-ethynyl-5--androstano[3,2-b]pyrimido[1,2-a]benzimidazole)
and WIN 62,577 (17--hydroxy- 17--ethynyl-
4-androstano[3,2-b]pyrimido[1,2-a]benzimidazole)
are potent and centrally active antagonists at rat, but not human,
NK1 receptors. The interactions of these compounds and some
analogs with [3H]N-methyl scopolamine
([3H]NMS) and unlabeled acetylcholine (ACh) at
M1-M4 muscarinic receptors have been studied
using equilibrium and nonequilibrium radioligand binding methods. The
results are consistent with the predictions of the allosteric ternary
complex model. The WIN compounds have log affinities for the unliganded
receptor in the range 5 to 6.7, and exhibit positive, negative, or
neutral cooperativity with [3H]NMS and ACh, depending on
the receptor subtype and nature of the interacting ligands. WIN 62,577 is an allosteric enhancer of ACh affinity at M3 receptors.
Although interacting allosterically, WIN 62,577 and WIN 51,708 do not
affect [3H]NMS dissociation from M3
receptors. Certain analogs have higher affinities than WIN 62,577, and
truncated forms of WIN 62,577, including steroids, also act
allosterically. One analog,
17--hydroxy-17--4-androstano[3,2-b]pyrido[2,3-b]indole
(PG987), has the unique effect of speeding [3H]NMS
dissociation; its largest effect, 2.5-fold, is at M3
receptors. The interaction between PG987 and other allosteric agents on
[3H]NMS dissociation from M3 receptors
indicate that PG987 binds reversibly to a site distinct from that to
which gallamine and strychnine bind: in contrast, PG987 seems to bind
to the same site on M3 receptors as KT5720, staurosporine,
and WIN 51,708. Therefore, in addition to the allosteric site that
binds strychnine (and probably chloromethyl brucine, another allosteric
enhancer) there is a second, nonoverlapping, pharmacologically distinct allosteric site on M3 receptors that also supports positive
cooperativity with ACh.
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