RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 303
OP 312
DO 10.1124/mol.115.100172
VO 89
IS 2
A1 Wood, Martyn
A1 Ates, Ali
A1 Andre, Veronique Marie
A1 Michel, Anne
A1 Barnaby, Robert
A1 Gillard, Michel
YR 2016
UL http://molpharm.aspetjournals.org/content/89/2/303.abstract
AB Agonists at dopamine D2 and D3 receptors are important therapeutic agents in the treatment of Parkinson’s disease. Compared with 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 that 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 orthosteric ligands, 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 electrophysiologic studies on dissociated striatal neurons and in vivo on the effects of l-dopa in the 6OHDA (6-hydroxydopamine) 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.