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Binding of [3H]AF-DX 384 to cloned and native muscarinic receptors

JH Miller, VA Gibson and M McKinney

Department of Pharmacology, Mayo Clinic Jacksonville, Florida.

The binding selectivity of [3H]AF-DX 384 [(+-)-5,11-dihydro-11- ([(2-(2- [(dipropylamino)methyl]-1- piperidinyl)ethyl)amino]carbonyl)-H- pyrido(2,3-b)(1,4)benzodiazepine-6-o ne] was evaluated with cloned human muscarinic receptors (M1-M4) in Chinese hamster ovary (CHO-K1) cell lines as well as in rat heart and brain. There were uniform classes of sites for the radioligand in the M2-rich tissues, heart (Kd = 2.3 nM) and brainstem (Kd = 2.4 nM). However, [3H]AF-DX 384 bound to all four cloned receptor subtypes. Using kinetic methods, the calculated Kd values were M2 (1 nm) greater than M4 (2.2 nM) greater than M3 (15 nM) greater than M1 (55 nM). Scatchard analysis with the CHO cells confirmed the high affinity of this radioligand for the M2 (1.8 nM) and M4 (2.5 nM) receptors. To evaluate the potential for selectively binding to M2 and M4 receptors in cortex and striatum, low concentrations (0.5-0.8 nM) of the radioligand were used and a two-site competition model was used to derive the binding constants for pirenzepine and AF-DX 116 [(+-)-11-2((-((diethylamino) methyl)-1- piperidinyl)acetyl)-5,11-dihydro-6H- pyrido(2,3-b)(1,4)-benzodiazepine- 6-one] and to compare them with values obtained with cloned M2 and M4 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 259, Issue 2, pp. 601-607, 11/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics




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