Synthesis toward Bivalent Ligands for the Dopamine D₂ and Metabotropic Glutamate 5 Receptors

Abstract

In this study, we designed and synthesized heterobivalent ligands targeting heteromers consisting of the metabotropic glutamate 5 receptor (mGluR5) and the dopamine D receptor (DR). Bivalent ligand 22a with a linker consisting of 20 atoms showed 4-fold increase in affinity for cells coexpressing DR and mGluR5 compared to cells solely expressing DR. Likewise, the affinity of 22a for mGluR5 increased 2-fold in the coexpressing cells. Additionally, 22a exhibited a 5-fold higher mGluR5 affinity than its monovalent precursor 21a in cells coexpressing DR and mGluR5. These results indicate that 22a is able to bridge binding sites on both receptors constituting the heterodimer. Likewise, cAMP assays revealed that 22a had a 4-fold higher potency in stable DR and mGluR5 coexpressing cell lines than 1. Furthermore, molecular modeling reveals that 22a is able to simultaneously bind both receptors by passing between the TM5-TM6 interface and establishing six protein-ligand H-bonds.

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…They all affect the MAPK response of these receptor systems, D1/D3 also modify recruitment of β-Arrestin-1 and heterodimer internalization. mGlu5/D2, D2/mu opioid receptor, D2/neurotensin 1 receptor, and D2/5-HT1a heterodimers have been also described, but not necessarily in the context of SCZ ( Lukasiewicz et al., 2016 ; Qian et al., 2018a ; Qian et al., 2018b ). They can all be potentially relevant for the effects of antipsychotic agents and for the generation of new ligands with unique pharmacological properties ( Hubner et al., 2016 ).…”

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

“…Thus, the receptor heteromer would be more likely to be disease-specific than would the corresponding monomeric/homomeric receptors” (Cortés et al, 2016). Newer reports show that heteromer-selective drugs can exist in the form of small-molecules, bivalent or multifunctional ligands, or antibodies, displaying higher affinity and efficacy for a receptor that forms a certain heteromer than for this receptor in another heteromer or in the monomeric form (Orru et al, 2011; Gomes et al, 2013c,b, 2016a; Cortés et al, 2016; Pulido et al, 2018; Qian et al, 2018a,b).…”

Design, Synthesis and Characterization of a New Series of Fluorescent Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulators

“…This afforded a concise series of six mGlu 5 R fluorescent ligands 4a-f ( Figure 2). The mGlu5R carboxylate derivatives were condensed with different spacers containing both an amine and azide terminus in the presence of the coupling agent EDC and triethylamine to yield six intermediate azides as described previously [19]. The synthesis of the desired fluorescent ligands was accomplished by reacting each of these azides with an alkyne-modified BODIPY red dye through CuAAC.…”

“…All ligands exhibited similar excitation and emission wavelengths with comparable spectral separation (~40 nm) between them (Figure 3a). Next, we assessed the fluorescence intensity by exciting ligands at 573 nm (the theoretical peak of excitation of BODIPY) and at 490 nm (the emission wavelength of The mGlu5R carboxylate derivatives were condensed with different spacers containing both an amine and azide terminus in the presence of the coupling agent EDC and triethylamine to yield six intermediate azides as described previously [19]. The synthesis of the desired fluorescent ligands was accomplished by reacting each of these azides with an alkyne-modified BODIPY red dye through CuAAC.…”

“…General procedure 1: Copper mediated azide-alkyne cycloaddition. To a solution of the azido-linker modifies MTEP analogues [19] (1.0 eq.) in dimethylformamide (0.1 M) was added the alkyne-modified BODIPY-red (1.5 eq.…”