Next Generation Analogues of SB269652 – A Negative Allosteric Modulator Targeting the Dopamine D2 Receptor

The dopamine D2 receptor (D2R) is a Family A G protein-coupled receptor (GPCR) and therapeutic target for schizophrenia and Parkinson’s disease. To date, drug discovery at this receptor has primarily focused on the development of ligands that compete for the orthosteric site where dopamine binds. More recently, GPCR research has extended toward the development of allosteric modulators that interact with a topographically distinct binding site to that occupied by the endogenous ligand. Allosteric drugs that target the D2R and act to tune down (Negative Allosteric Modulator, NAM) the action of dopamine may present a safer, more effective way, to treat schizophrenia.

This approach has yet to be exploited due to the lack of drug-like allosteric modulators of the D2R. SB269652 was recently identified as the first small molecule NAM of the D2R displaying an affinity of 776 nM and moderate negative cooperativity with dopamine (AlphaBeta = 0.059, conferring a maximal 17-fold decrease in dopamine potency). This compound was shown to bind the receptor in a bitopic manner whereby the 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (7CN-THIQ) "head" group occupies the orthosteric site and the cyclohexylene "linker" and the indole-2-carboxamide “tail” extend into a secondary binding pocket. We aim to synthesize a series of ‘next generation’ analogues of the bitopic ligand SB269652 by varying the "tail" to identify additional key molecular features that are responsible for changes in affinity and negative allosteric cooperativity. This information will further enhance our understanding of the nature of this allosteric mechanism at the D2R and potentially provide an avenue to a novel therapeutic class for the treatment of schizophrenia.