Receptor Reserves at α2-adrenergic and Dopaminergic Autoreceptors
Repeated observations that the maximal response elicited by an agonist can be obtained when only a fraction of receptors are occupied has led to the concept of “spare receptors” (or “receptor reserve”). A large pool of “spare receptors” has been found in many peripheral tissues and partial agonists with substantial, but submaximal, intrinsic efficacy often produce maximal response (Nickerson 1956; Stephenson 1956; Ariens et al., 1960). The law of mass action relates fractional occupancy to ligand concentration and it follows that a lower agonist concentration will suffice to elicit a particular level of response the greater the excess of functional receptors (larger receptor reserve). In order to delineate the relationship between receptor occupancy and closely coupled physiologic responses at α2-adrenergic and dopaminergic autoreceptors, we have inactivated a portion of these receptors with the recently described irreversible antagonist Nethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ) (Meller et al., 1985). This compound was found to dose-dependently inactivate central α2-adrenrgic and dopaminergic receptors in vivo.
KeywordsDopamine Agonist Maximal Response Receptor Occupancy Receptor Binding Site Dopamine Receptor Agonist
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- Ariens, E.J., Van Rossum, J.M. and Koopman, P.C. (1960). Receptor reserve and threshold phenomena. Arch. Int. Pharmacodyn Ther. 127, 459–478.Google Scholar
- Furchgott, R.F. (1966). The use of beta-haloalkylamines in the differentiation of receptors and in the determination of dissociation constants of receptor-agonist complexes. Adv. Drug Res. 3, 21–55.Google Scholar
- Goldstein, M., Helmer, E. and Fuxe, K. (1984). Effects of dopamine agonists on presynaptic normosensitive and on postsynaptic supersensitive DA receptors. IUPHAR 9th International Congress of Pharmacology, Abstr. 1155P.Google Scholar
- Mauger, J.P., Sladeczek, F. and Bockaert, J. (1982). Characteristics and metabolism of alphal adrenergic receptors in a nonfusing muscle cell line. J. Biol. Chem. 257, 875–879.Google Scholar
- Meller, E., Bohmaker, K., Goldstein, M. and Friedhoff, A.J. (1985). Inactivation of D1 and D2 dopamine receptors by Nethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline in vivo. J Pharm. Exp. Ther. 233, 656–662.Google Scholar
- Minneman, K.P. and Abel, P.W. (1984). Spare alphaladrenergic receptors and the potency of agonists in rat vas deferens. Mol. Pharmacol. 25, 56–62.Google Scholar
- Roth, R.H. (1979). Dopamine autoreceptors: pharmacology, function and comparison with post-synaptic dopamine receptors. Commun. Psychopharmacol. 5, 49.Google Scholar
- Schoffelmeer, A.N.M., Hoorneman, E.M.D., Sminia, P. and Mulder, A.H. (1984). Presynaptic a2 and postsynaptic Badrenoreceptor sensitivity in slices of rat neocortex after chronic treatment with various antidepressant drugs. Neuropharm. a, 115–120.Google Scholar
- Stephenson, R.P. (1956). A modification of receptor theory. Br. J. Pharmacol. 11:379–393.Google Scholar