Dopamine receptor agonists: intrinsic activity vs. state of receptor

Abstract

Based on observations with the novel dopamine-receptor agonist 3-(3-hydroxyphenyl-)-N-n-propylpiperidine, 3-PPP, especially its levorotatory enantiomer, it is proposed that the intrinsic activity of a receptor agonist depends in part on the responsiveness of the receptor; this in turn is determined by the degree of previous agonist occupancy on the receptor. A change in occupancy will induce a slow conformational change, influencing the responsiveness. This may constitute an important aspect of receptor adaptation and may help to explain otherwise puzzling phenomena, e.g. that compounds such as (-)-3-PPP or transdihydrolisuride can act as strong dopamine-receptor agonists in some locations and as antagonists in others. The observations discussed in the present paper may be interpreted to indicate that the dopamine receptors in different locations are, in fact, derived from a homogenous receptor population, though in a varying state of adaptation. Thus it may prove worth-while to reconsider the various subclassifications of DA receptors proposed so far.