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Vol. 57, Issue 3, 436-445, March 2000

Allosteric Interactions between the Antagonist Prazosin and Amiloride Analogs at the Human alpha 1A-Adrenergic Receptor1

Ray A. Leppik,2 Anita Mynett,2 Sebastian Lazareno, and Nigel J. M. Birdsall

National Institute for Medical Research, The Ridgeway, Mill Hill, London (R.A.L., A.M., N.J.M.B.); and Medical Research Council Collaborative Centre, London, United Kingdom (S.L.)

It has been demonstrated previously that amilorides can interact with a well defined allosteric site on the human alpha 2A-adrenergic receptor. In this study, the question was explored as to whether the human alpha 1A-adrenergic receptor also possesses an equivalent allosteric site. The six amilorides examined strongly increased the dissociation rate of the antagonist [3H]prazosin from the alpha 1A-adrenergic receptor in a concentration-dependent manner. With the parent amiloride, the dissociation data were well fitted by an equation derived from the ternary complex allosteric model, compatible with amiloride acting at a defined allosteric site on the alpha 1A-adrenergic receptor. In contrast, the dissociation data for [3H]prazosin in the presence of the amiloride analogs were not compatible with the equation derived from a one-allosteric-site model, but could be fitted well by an equation derived from a two-allosteric-site model. However, certain individual parameters could not be resolved. The observed dissociation rate constants increased steeply with increasing amiloride analog concentration, and in some cases the data could be fitted with a logistic equation. The slope factors calculated from such fits were 1.2 to 2.1. It is concluded that the structure-binding relationships of the amilorides at the alpha 1A- and alpha 2A-adrenergic receptors are different. The interactions of the five amiloride analogs, but not the parent amiloride, with the alpha 1A-adrenergic receptor are compatible with the presence of two (but not one) allosteric sites, and is thus more complex than that found for the alpha 2A-adrenergic receptor.

1 A preliminary report of the work described in this article was presented at the XIIIth International Congress of Pharmacology, 1998 (Leppik et al., 1998b).

2 R.A.L. and A.M. are recipients of a ROPA research grant.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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