Receptor partial allosteric modulators

FIGURE 10.19 Patterns of insurmountable blockade of receptors under conditions of (a) hemi-equilibria and (b) allosteric modulation by a modulator that only partially reduces receptor signaling, (a) Concentration-response curves to the full agonist are shifted to the right in a concentration-dependent manner. The maximal response is partially depressed and may attain a plateau level, (b) Curves are shifted to a limiting value characteristic of saturable allosteric modulation. In addition, the maximal response is depressed to a new asymptote. Note that the maximal response is not blocked to basal levels indicative of >0 (see Section 7.8.2 and Equation 7.3). 

Maksay, G., Thompson, S. A., and Wafford, K. A. (2000) Allosteric modulators affect the efficacy of partial agonists for recombinant GABA(A) receptors. Br. J. Pharmacol. 129, 1794-1800. 

Guerciohni R, Szumlanski C, Weinshilboum RM Human liver xanthine oxidase nature and extent of individual variation. Chn Pharmacol Ther 50 663-672, 1991 Guisti P, Ducic I, Puia G, et al Imidazenil a new partial positive allosteric modulator of gamma-amniobutyiic acid (GABA) action of GABAa receptors. J Pharmacol Exp Ther 266 1018-1028, 1993... 

There is no specific reason for an allosteric modulator to completely inhibit receptor activation. Receptor function may partially be modulated (1 < > 0) or even increased ( , > 1). To consider an increase in efficacy first, on the surface it might be expected that an increase in efficacy would result in an increase in the maximal response, and in systems where the agonists are not full agonists (stimulus does not saturate the stimulus-response capability of... 

Galanthamine is the only alkaloid of this class that has already found apphcation in medicine. It is approved for the symptomatic treatment of Alzheimer s disease in Europe and the United States. Its mode of action consists in a competitive and reversible inhibition of acetylcholinesterase, which leads to an increased concentration of acetylcholine at neuronal synapses. In addition, galanthamine acts as an allosteric modulator on nicotinic acetylcholine receptors. Since a characteristic featnre of Alzheimer s disease is the loss of acetylcholinergic neurons concomitant with decreased levels of acetylcholine, galanthamine can, at least partially, compensate the damage and thus enhance cognitive functions in Alzheimer s patients. 

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