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Vol. 53, Issue 5, 916-925, May 1998
2A-Adrenergic Receptor
National Institute for Medical Research, London NW7 1AA, UK
(R.A.L., A.M., N.J.M.B.) and
Medical Research Council Collaborative
Centre, London NW7 1AD, UK (S.L.)
The purpose of this study was to determine whether there is a
well-defined allosteric site on the human 
2A-adrenergic
receptor. To explore this question, we examined the effects of
amiloride analogues on the dissociation of [3H]yohimbine,
[3H]rauwolscine, and [3H]RX821002. The
dissociation data fitted well to an equation derived from the ternary
complex allosteric model with amiloride analogue concentration and time
as two independent variables. The estimated maximal increase in the
[3H]yohimbine dissociation rate caused by the
5-N-alkyl amilorides varied from 2-fold for the parent
amiloride to 140- and 160-fold for
5-(N,N-hexamethylene)-amiloride and
5-(N-ethyl-N-isopropyl)-amiloride, respectively. The calculated log affinities at the yohimbine-occupied receptor ranged from 1.75 for
5-(N-ethyl-N-isopropyl)-amiloride to 2.5 for 5-(N,N-hexamethylene)-amiloride. The
increase in affinity found at the yohimbine-occupied receptor was not
correlated with increase in size of the 5-N-alkyl side
chain, in contrast to the situation found at the unoccupied receptor.
The effect of competition between two amilorides on yohimbine
dissociation also was explored. The data obtained were well fitted by
the equation derived from the relevant model, with the off-rate
increases caused by
5-(N,N-hexamethylene)-amiloride being
either decreased or increased by the competing amiloride analogue in
line with predictions, and the parameters derived from the fits were in
good agreement with those obtained in the above dissociation assays.
Thus, the data are compatible with the amilorides competing at the one
allosteric site on the 2A-adrenergic receptor and rules
out the possibility that the amilorides are acting in a nonspecific
fashion.
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