Both extracellular and transmembrane residues contribute to the species selectivity of the neurokinin-1 receptor antagonist WIN 51708

BS Sachais and JE Krause

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110.

WIN 51708 is a nonpeptide antagonist of the neurokinin (NK)-1 (substance P) receptor that possesses a dramatically higher affinity for the rat NK-1 receptor, compared with the human NK-1 receptor. This selectivity is the opposite of the selectivity displayed by CP-96,345 and is much greater in magnitude than the selectivity of RP 67580. The naturally occurring peptide agonist substance P shows no such species selectivity. To determine the molecular basis for the species selectivity of WIN 51708, a series of chimeric and point-mutated NK-1 receptors were created and functionally expressed in Chinese hamster ovary cells. Residue 97 in the first extracellular loop and residue 290 in the seventh putative transmembrane domain are critical determinants for the selectivity of WIN 51708 for the rat over the human NK-1 receptor. Although mutation of either residue 97 or residue 290 in the rat NK-1 receptor is sufficient for a low, human-like affinity for WIN 51708, both of these residues must be simultaneously mutated in the human NK-1 receptor to allow nearly rat wild-type affinity for this antagonist. This suggests that the binding environment for WIN 51708 in the rat NK-1 receptor differs, at least in part, from the binding environment in the human NK-1 receptor. In addition, although residue 290 is critical for the species selectivity of WIN 51708 and CP-96,345, residue 97 does not play a role in the species selectivity of CP- 96,345. These data support a model in which the binding environments for WIN 51708 and CP-96,345 in part differ.

Volume 46, Issue 1, pp. 122-128, 07/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				S. M. Gopalakrishnan, B. Mammen, M. Schmidt, B. Otterstaetter, W. Amberg, W. Wernet, J. L. Kofron, D. J. Burns, and U. Warrior An Offline-Addition Format for Identifying GPCR Modulators by Screening 384-Well Mixed Compounds in the FLIPR J Biomol Screen, February 1, 2005; 10(1): 46 - 55. [Abstract] [PDF]

				S. Lazareno, A. Popham, and N. J. M. Birdsall Analogs of WIN 62,577 Define a Second Allosteric Site on Muscarinic Receptors Mol. Pharmacol., December 1, 2002; 62(6): 1492 - 1505. [Abstract] [Full Text] [PDF]

				J. E. Krause, P. T. Staveteig, J. N. Mentzer, S. K. Schmidt, J. B. Tucker, R. M. Brodbeck, J.-Y. Bu, and V. V. Karpitskiy Functional expression of a novel human neurokinin-3 receptor homolog that binds [3H]senktide and [125I-MePhe7]neurokinin B, and is responsive to tachykinin peptide agonists PNAS, January 7, 1997; 94(1): 310 - 315. [Abstract] [Full Text] [PDF]

				D. Shire, B. Calandra, M. Delpech, X. Dumont, M. Kaghad, Gér. Le Fur, D. Caput, and P. Ferrara Structural Features of the Central Cannabinoid CB1 Receptor Involved in the Binding of the Specific CB1 Antagonist SR 141716A J. Biol. Chem., March 22, 1996; 271(12): 6941 - 6946. [Abstract] [Full Text] [PDF]