The First Negative Allosteric Modulator for Dopamine D 2 and D 3 Receptors SB269652 May Lead to a New Generation of Antipsychotic Drugs MOL #107607 2 RUNNING TITLE PAGE Running title: Allosteric modulators as new generation antipsychotics

Until recently, the only strategy to develop drugs regulating GPCR activity was through the identification of compounds that directly acted on the orthosteric sites for endogenous ligands. However, many efforts have recently been made in order to identify small molecules that are able to interact with allosteric sites. These sites are less well-conserved; therefore, allosteric ligands have greater selectivity on the specific receptor. Strikingly, the use of allosteric modulators can provide specific advantages, such as an increased selectivity for GPCR subunits and the ability to introduce specific beneficial therapeutic effects without disrupting the integrity of complex physiologicallyregulated networks. In 2010, our group unexpectedly found that SB269652, a compound supposed to interact with the orthosteric binding site of dopamine receptors, was actually a negative allosteric modulator of D 2 and D 3 receptor dimers, thus identifying the first allosteric small molecule acting on these important therapeutic targets. This review addresses the progresses in the understanding of the molecular mechanisms of interaction between the negative modulator SB269652 and D 2 and D 3 dopamine receptor monomers and dimers, and also the perspectives of developing new dopamine receptor allosteric drugs based on SB269652 as the leading compound