TY - JOUR T1 - In-Vitro and In-Vivo Identification of Novel Positive Allosteric Modulators of the Human Dopamine D2 and D3 Receptor JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.115.100172 SP - mol.115.100172 AU - Martyn Wood AU - Ali Ates AU - Veronique Andre AU - Anne Michel AU - Robert Barnaby AU - Michel Gillard Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/early/2015/12/11/mol.115.100172.abstract N2 - Agonists at dopamine D2 and D3 receptors are important therapeutic agents in the treatment of Parkinson's disease. Compared to the use of agonists, allosteric potentiators offer potential advantages such as temporal, regional and phasic potentiation of natural signaling, and that of receptor subtype selectivity. We report the identification of a stereoselective interaction of a benzothiazol racemic compound which acts as a positive allosteric modulator (PAM) of the rat and human dopamine D2 and D3 receptors. The R-isomer did not directly stimulate the dopamine D2 receptor but potentiated the effects of dopamine. In contrast the S-isomer attenuated the effects of the PAM and the effects of dopamine. In radioligand binding studies, these compounds do not compete for binding of the orthosteric ligand, but indeed the R-isomer increased the number of high affinity sites for [3H]-dopamine without affecting Kd. We went on to identify a more potent PAM for use in native receptor systems. This compound potentiated the effects of D2/D3 signaling in-vitro in electrophysiological studies on dissociated striatal neurons and in-vivo on the effects of L-Dopa in the 6-OHDA contralateral turning model. These PAMs lacked activity at a wide variety of receptors, lacked PAM activity at related Gi - coupled G protein-coupled receptors and lacked activity at D1 receptors. However, the PAMs did potentiate [3H]-dopamine binding at both D2 and D3 receptors. Together, these studies show that we have identified PAMs of the D2 and D3 receptors both in-vitro and in-vivo. Such compounds may have utility in the treatment of hypodopaminergic function. ER -