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The First Negative Allosteric Modulator for Dopamine D2 and D3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs - PubMed Skip to main page content
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Review
. 2017 Jun;91(6):586-594.
doi: 10.1124/mol.116.107607. Epub 2017 Mar 6.

The First Negative Allosteric Modulator for Dopamine D2 and D3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs

Mario Rossi  1 , Irene Fasciani  1 , Francesco Marampon  1 , Roberto Maggio  2 , Marco Scarselli  2
Affiliations
Review

The First Negative Allosteric Modulator for Dopamine D2 and D3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs

Mario Rossi et al. Mol Pharmacol. 2017 Jun.

Abstract

D2 and D3 dopamine receptors belong to the largest family of cell surface proteins in eukaryotes, the G protein-coupled receptors (GPCRs). Considering their crucial physiologic functions and their relatively accessible cellular locations, GPCRs represent one of the most important classes of therapeutic targets. 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 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 physiologically regulated networks. In 2010, our group unexpectedly found that N-[(1r,4r)-4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1H-indole-2-carboxamide (SB269652), a compound supposed to interact with the orthosteric binding site of dopamine receptors, was actually a negative allosteric modulator of D2- and D3-receptor dimers, thus identifying the first allosteric small molecule acting on these important therapeutic targets. This review addresses the progress in understanding the molecular mechanisms of interaction between the negative modulator SB269652 and D2 and D3 dopamine receptor monomers and dimers, and surveys the prospects for developing new dopamine receptor allosteric drugs with SB269652 as the leading compound.

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Figures

Fig. 1.
Fig. 1.
Schematic representation of the allosteric binding modes of SB269652 to dopamine receptor dimer and monomer. SB269652 is represented with its three main parts, the 7CN-THIQ group (pink), the trans-cyclohexylene spacer in the middle, and the indole-2-carboxamide tail (sky blue). In the left part of the image, SB269652 is shown bind in a bitopic mode to one protomer of the dopamine dimer, the 7CN-THIQ group to the orthosteric site (Orth), and the indole-2-carboxamide group to the allosteric site (All1), and exert an allosteric effect across dimer on dopamine sitting on the orthosteric site of the other protomer (Lane et al., 2014). In the right part of the image, SB269652 is shown bind to a dopamine-occupied monomer and prevent the dissociation of dopamine from the same receptor. In this configuration, the indole-2-carboxamide group would bind to the allosteric site as shown for SB269652 in the bitopic pose (All1), and the 7CN-THIQ group would engage an additional site on the extracellular part of the receptor (All2). This second arrangement of SB269652 on the dopamine-occupied receptor would be unfavorable in respect to the bitopic binding mode and would occur only for high doses of the drug.
Fig. 2.
Fig. 2.
Chemical structure of optimized SB269652 analogs. Value of KB (functional affinity) and αβ (allosteric cooperativity with dopamine) were taken from Shonberg et al. (2015) and Mistry et al. (2015). The part of the molecule boxed in pink binds to the orthosteric site, whereas the part boxed in light blue binds to the allosteric site. For comparison we added a compound (25d) lacking an allosteric effect.
See this image and copyright information in PMC

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