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Aminopyridazine muscarinic agonist, SR 95639A, is a functional M 2 receptor antagonist in rat brain
Author(s) -
Anderson David J.,
Decker Michael W.,
Arneric Stephen P.,
Cadman Evelyn,
Buckley Michael J.,
VellaRountree Lorraine,
Williams Michael
Publication year - 1991
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430240109
Subject(s) - carbachol , muscarinic acetylcholine receptor , agonist , chemistry , endocrinology , medicine , muscarinic agonist , muscarinic acetylcholine receptor m1 , muscarinic antagonist , muscarinic acetylcholine receptor m3 , receptor , antagonist , receptor antagonist , oxotremorine , partial agonist , inositol phosphate , muscarinic acetylcholine receptor m2 , pharmacology , inositol , biology , biochemistry
The minaprine analog SR 95639A (morpholinoethylamino‐3‐benzocylohepta‐(5,6‐c)pyridazine dihydrochloride), a putative muscarinic M 1 receptor agonist, was evaluated for muscarinic activity in a number of biochemical and behavioral tests. Binding studies indicated that SR 95639A was 4‐fold selective for the M 1 receptor. In contrast, both carbachol and the Merck “super agonist,” L 670,207, were 50‐fold selective for the M 2 receptor, with Ki values of 47 μM and 100nM at the M 1 receptor and 1 μM and 2nM at the M 2 receptor, respectively. At concentrations up to 1 mM, SR 95639A had no effect on M 1 receptor‐evoked phosphatidyl inositol (Pl) hydrolysis, while carbachol and L 670,207 had EC 50 values of 116±10 μM and 0.60±0.12 μM respectively. SR 95639A (100 μM) did not inhibit the Pl response elicited by carbachol. At striatal M 2 receptors linked to inhibition of forskolin‐mediated cyclic AMP production, SR 95639A at concentrations up to 100 μM had no agonist activity, while carbachol and L 670,207 had respective EC 50 values of 540±31 nM and 2.9±0.5 nM. However, SR 95639A was an effective antagonist (K app = 3.50±0.45 μM; n = 5) of the carbachol response. In a rat radial arm maze paradigm, SR 95639A did not enhance cognitive performance and was unable to reverse deficits induced by scopolamine. The compound produced a dose‐dependent increase in mouse locomotor activity and did not attenuate the effects of scopolamine on habituation, but did potentiate oxotremorineinduced hypothermia.