Hoare, S.R.J. and Coldwell, M.C. and Armstrong, C. and Strange, P.G. (2000) Regulation of human D-1, D-2(long), D-2(short), D-3 and D-4 dopamine receptors by amiloride and amiloride analogues. British Journal of Pharmacology, 130 (5). pp. 1045-1059. ISSN 0007-1188.
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1 The modulatory effects of the allosteric effecters methylisobutylamiloride (MIA), benzamil and amiloride have been examined at human D-1, D-2, D-3 and D-4 dopamine receptors. The subtype selectivity and the mechanism of action of this allosteric regulation was examined. 2 In radioligand dissociation experiments each modulator accelerated dissociation from all four receptor subtypes indicating allosteric regulation. MIA displayed selectivity for the D-3 subtype for acceleration of radioligand dissociation. 3 In equilibrium binding (pseudo-competition) experiments the three compounds inhibited radioligand binding at the four receptor subtypes. Inhibition curves for D-1, D-2(short), D-2(long) and D-3 receptors were described by Hill coefficients exceeding unity and data were fitted best by a model that assumes binding of modulator to both the primary and allosteric binding sites of the receptor (the allosteric/competitive model). 4 At the D-4 subtype, Hill coefficients of unity described the binding data for amiloride and benzamii, consistent with competitive inhibition. The Hill coefficient for MIA at the D-4 subtype was less than unity and data could be fitted well by the allosteric/competitive model, but it was not possible to define unambiguously the modulatory mechanism. For this effect a better definition of the mechanism could be obtained by simultaneous analysis of data obtained in the presence of a range of concentrations of a purely competitive ligand. 5 MIA reduced the potency with which dopamine stimulated [S-35]-GTP gamma S binding at: the D-2 receptor. The effects of MIA could be described by the allosteric/competitive model with effects of MIA to inhibit the binding of dopamine but not its ability to induce a response.
|Uncontrolled keywords:||dopamine receptors (D-1,D-2, D-3, D-4); allosteric regulation; amiloride; radioligand dissociation; radioligand binding|
R Medicine > RS Pharmacy and materia medica
|Divisions:||Faculties > Science Technology and Medical Studies > School of Biosciences|
|Depositing User:||O.O. Odanye|
|Date Deposited:||03 Apr 2009 10:25|
|Last Modified:||24 Apr 2012 13:24|
|Resource URI:||http://kar.kent.ac.uk/id/eprint/16216 (The current URI for this page, for reference purposes)|
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