Positive allosteric modulators

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

Knoflach, F., Mutel, V., Jolidon, S., et al. (2001) Positive allosteric modulators of metabotropic glutamate 1 receptor characterization, mechanism of action, and binding site. Five. Natl. Acad. Sci. USA 98,13402-13407. 

Flor, P. J., Maj, M., Dragic, Z., et al. (2002) Positive allosteric modulators of metabotropic glutamate receptor subtype 4 pharmacological and molecular characterization. Neuropharmacology 43, 286. 

Mathiesen, J. M., Svendsen, N., Brauner-Osbome, H., Thomsen, C., and Ramirez, M. T. (2003) Positive allosteric modulation of human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP. Br. J. Pharmacol. 138,1026-1030. 

Hu, J., Reyes-Cruz, G., Chen, W., Jacobson, K. A., and Spiegel, A. M. (2002) Identification of acidic residues in the extracellular loops of the seven-transmembrane domain of the human Ca2+ receptor critical for response to Ca2+ and a positive allosteric modulator. J. Biol. Chem. 277,46622-46631. 

Fig. 1. Chemical structures of ligands used to characterize, clone, and purify the GABAb receptor. The recently identified positive allosteric modulators CGP7930 and CGP 13501 are expected to broaden the spectrum of therapeutic applications for GABAb drugs.

Pin, J. P, Parmentier, M. L and Prezeau, L. (2001) Positive allosteric modulators for gamma-aminobutyric acidB receptors open new routes for the development of drugs targeting family 3 G protein-coupled receptors. Mol. Pharmacol. 60, 881-884. 

Urwyler, S Mosbacher, J Lingenhoehl, K., et al. (2001) Positive allosteric modulation of native and recombinant gamma-aminobutyric acidB receptors by 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501. Mol. Pharmacol. 60,963-971. 

Maj M, Bruno V, Dragic Z, et al (2003) (-)-PHCCC, a positive allosteric modulator of mGluR4 characterization, mechanism of action, and neimoprotection. Netuopharma-cology 45 895-906... 

While no data on the role of 3a-reduced neuroactive steroids in PTSD or its treatment in panic disorder patients have been pubhshed to date, opposite changes to those seen in major depression have emerged. At baseline, patients with panic disorder had significantly increased concentrations of the positive allosteric modulators 3a,5a-THP and 3a,5P-THP, together with sig-... 

The main effects of BZs occur via positive allosteric modulation. The BZs and GABA bind to separate sites on the GABAa receptor complex. When a BZ occupies the BZ receptor, GABA s ability to open the chloride channels increases. With greater opening of the chloride channel, cellular excitability decreases (Ballenger, 1995). The final result of this decreased cellular excitability is widespread because of the extensive inhibitory role of GABA in the CNS. As a result, BZs may alter the turnover of neurotransmitters such as norepinephrine and serotonin (5-hydroxytryptamine [5-HT]). 

Another receptor system with which neurosteroids interact is the N-methyl-D-aspartate [NMDA] receptor. Pregnenolone sulfate acts as a positive allosteric modulator of the NMDA receptor, in analogy to GABA-ergic effects, by increasing the frequency and duration of NMDA-activated channel opening [Bowlby 1993 Irwin et al. 1992 Wu et al. 1991]. 

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... 

Pyruvate carboxylase is a regulatory enzyme and is virtually inactive in the absence of acetyl-CoA, its positive allosteric modulator. Whenever acetyl-CoA, the fuel for the citric acid cycle, is present in excess, it stimulates the pyruvate carboxylase reaction to produce more oxaloacetate, enabling the cycle to use more acetyl-CoA in the citrate synthase reaction. 

Regulation of Pyruvate Carboxylase The carboxy-lation of pyruvate by pyruvate carboxylase occurs at a very low rate unless acetyl-CoA, a positive allosteric modulator, is present. If you have just eaten a meal rich in fatty acids (tri-acylglycerols) but low in carbohydrates (glucose), how does this regulatory property shut down the oxidation of glucose to C02 and H20 but increase the oxidation of acetyl-CoA derived from fatty acids ... 

To understand both positive allosteric modulation and negative allosteric modulation. 

Because AMPA receptors function in concert with NMDA receptors, they have been proposed as alternative therapeutic targets in schizophrenia. AMPAkines function as positive allosteric modulators of AMPA receptor-mediated neurotransmission, and facilitate learning and memory in both human (Ingvar et al., 1997) and animal (Hampson et al., 1998) models. Further, these drugs act synergistically with antipsycho-tics to reverse amphetamine-induced hyperactivity (Johnson et al., 1999). 

Lecourtier L, Homayoun H, Tamagnan G, Moghaddam B. 2007. Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex. Biol Psychiatry 62 739-746. 

Liu F, Grauer S, Kelley C, Navarra R, Graf R, et al. 2008. ADX47273 A novel metabotropic glutamate receptor 5 selective positive allosteric modulator with preclinical antipsychotic-like and pro-cognitive activities. J Pharmacol Exp Ther 327 827-839. 

Hurst RS, Hajos M, Raggenbass M, Wall TM, Higdon NR, et al. 2005. A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor In vitro and in vivo characterization. J Neurosci 25 4396-4405. 

Positive allosteric modulators of GABA effect increase in Cl conductance hyperpolarization — decreased excitability... 

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