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Vol. 58, Issue 5, 1091-1099, November 2000
2A-Adrenoceptor: Allosteric Modulation by Amilorides
National Institute for Medical Research, London, United Kingdom
It has been found previously that amilorides act via an allosteric site
on the 
2A-adrenergic receptor to strongly inhibit antagonist binding. In this study, allosteric modulation of agonist binding and function at the 2A-adrenergic receptor was
explored. The dissociation rate of the agonist
[3H]UK14304 from 2A-receptors was
decreased by the amilorides in a concentration-dependent manner. This
contrasts with the increases in 3H-antagonist dissociation
rate found previously. The agonist-amiloride analog interaction data
could be fitted to equations derived from the ternary complex
allosteric model. The calculated log affinities of the amilorides at
the [3H]UK14304-occupied receptor increased with the size
of the 5-N-alkyl side chain and ranged from 2.4 for
amiloride to 4.2 for 5-(N,N-hexamethylene)-amiloride. The calculated negative cooperativities cover a narrow range, in sharp
contrast to the broad range found for antagonist-amiloride analog
interactions. The effects of the amilorides on the agonist actions of
UK14304, epinephrine, and norepinephrine were explored using a
[35S]GTP
S functional assay, and the parameters
calculated for the cooperativities and affinities of the
UK14304-amiloride analog interactions, using the equation derived from
the ternary complex allosteric model, were in good agreement with those
derived from the kinetic studies. Therefore both the binding and
functional data provide further support for the existence of a well
defined allosteric site on the human 2A-adrenergic
receptor. The binding mode of the amilorides at the agonist-occupied
and antagonist-occupied receptor differs markedly but, within each
group, the structure of either the agonist or the antagonist examined
has only a slight effect on the allosteric interactions.
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