PubMed · 79317
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A Doenicke, W Lorenz, P Hug. 1978. [Histamine and etomidate].. https://pubmed.ncbi.nlm.nih.gov/79317/
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The effects of prolonged exposure of M(2) muscarinic acetylcholine receptors (mAChRs), stably expressed in Chinese hamster ovary cells, to the allosteric modulators gallamine, alcuronium, and heptane-1,7-bis (dimethyl-3'-phthalimidopropyl)-ammonium bromide (C(7)/3'-phth) were compared with the effects of the agonist carbachol (CCh) and antagonists atropine and N-methylscopolamine (NMS). Intact cell saturation binding assays using [(3)H]NMS found that pretreatment of the cells for 24 h with CCh caused a significant down-regulation of receptor number, whereas atropine, NMS, and all three allosteric modulators caused receptor up-regulation. Functional assays using a cytosensor microphysiometer to measure whole-cell metabolic rate found no acute effects of gallamine on receptor signaling, whereas atropine seemed to behave as an inverse agonist. Pretreatment of the cells with gallamine (20 microM) or atropine (20 nM) resulted in a significant enhancement of the maximal effect evoked by CCh. In contrast, CCh (100 microM) pretreatment resulted in a significant reduction in maximal receptor signaling capacity. Time-course experiments revealed that the effects of atropine and gallamine on receptor up-regulation are only visualized after at least 12-h ligand exposure, compared with the more rapid effects of CCh, which achieve steady-state down-regulation within 90 min. Additional experiments monitoring CCh-mediated M(2) mAChR internalization in the presence of gallamine revealed that part of the mechanism underlying the effects of the modulator on receptor expression may involve a change in receptor internalization properties. These findings suggest that, like orthosteric ligands, G protein-coupled receptor allosteric modulators also are able to mediate long-term effects on receptor regulation.
Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more 'physiological' regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validation of allosteric ligands.
Allosterism, whereby small molecule ligands produce global changes in the conformations of receptors, is a powerful mechanism for drug effect. This is illustrated by the recent data describing CCR5 antagonists as blockers of HIV infection. Allosteric effects are described in terms of a change in the tertiary conformation of the receptor. This paper outlines some unique features of allosteric antagonists as new drug entities. These include the fact that allosteric ligands have texture in antagonism (not all allosterically blocked receptors are alike), allosteric blockade is probe dependent (not all agonists and radioligands are blocked equally), and the fact that allosteric binding involves a separate site on the receptor may have relevance to duration of effect and selectivity. Dissociation between receptor function and binding also can be encountered with allosteric ligands.