New insights into receptor theory, as provided by an artificial partial agonist made-to-measure

Abstract

In the present study a mixture of a full agonist (noradrenaline) and a full antagonist (yohimbine) was used to mimic the effects of a partial agonist (clonidine) on alpha 2-autoreceptor-mediated regulation of noradrenaline release in order to learn more about the shape of concentration-response curves in the absence and presence of spare receptors. The sigmoidal shape of the cloud of single experimental data points may be reflected by different curve fits based on either descriptive or mechanistic mathematical models. Only mechanistic models allow the interpretation of the relationship between occupancy of receptors and induced response. The experiments were performed in rat neocortex and in rabbit hippocampus tissue where electrical field stimulation with 4 pulses/100 Hz of slices prelabelled with [3H]noradrenaline elicited the release of noradrenaline. A receptor reserve was found in the rabbit hippocampus and quantified from the concentration-response curve of noradrenaline in this tissue using a mechanistic general response function, developed to reflect the condition of spare receptors. The mixture of noradrenaline and yohimbine, NA-Yoh, (three parts to one part), corrected by the different affinities to the alpha 2-autoreceptors, was designed to mirror the quantified proportion of 75% non-spare and 25% spare alpha 2-autoreceptors. In the spare receptor-free rat cortex NA-Yoh acted like a typical partial agonist, as clonidine, with nearly the same EC50 (= Kd in this case) as the full agonist noradrenaline, but with a maximum effect significantly lower than that of noradrenaline. In the rabbit hippocampus, however, the same maximum effect was obtained with NA-Yoh, noradrenaline and clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)