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Review
. 2023 Jul 13:14:1222158.
doi: 10.3389/fphar.2023.1222158. eCollection 2023.

Neuroprotection afforded by targeting G protein-coupled receptors in heteromers and by heteromer-selective drugs

Rafael Franco  1   2   3 , Gemma Navarro  2   4   5
Affiliations
Review

Neuroprotection afforded by targeting G protein-coupled receptors in heteromers and by heteromer-selective drugs

Rafael Franco et al. Front Pharmacol. .

Abstract

G protein-coupled receptors (GPCRs) are the target of hundreds of approved drugs. Although these drugs were designed to target individual receptors, it is becoming increasingly apparent that GPCRs interact with each other to form heteromers. Approved drug targets are often part of a GPCR heteromer, and therefore new drugs can be developed with heteromers in mind. This review presents several strategies to selectively target GPCRs in heteromeric contexts, namely, taking advantage of i) heteromer-mediated biased agonism/signalling, ii) discovery of drugs with higher affinity for the receptor if it is part of a heteromer (heteromer selective drugs), iii) allosteric compounds directed against the interacting transmembrane domains and, eventually, iv) antagonists that block both GPCRs in a heteromer. Heteromers provide unique allosteric sites that should help designing a new type of drug that by definition would be a heteromer selective drug. The review also provides examples of rhodopsin-like class A receptors in heteromers that could be targeted to neuroprotect and/or delay the progression of diseases such as Parkinson's and Alzheimer's. GPCRs in heteromers (GriH) with the potential to address dyskinesias, a common complication of dopaminergic replacement therapy in parkinsonian patients, are also described.

Keywords: GPCR; biased agonism; drug discovery; heteromer imprint; heteromer selective drug; neurodegeneration; neuronal death.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Heteromer-selective compounds. Panel (A). The heteromer selective compound (orange) interacts with low affinity with the two GPCRs (blue and red). Panel (B). The compound (orange) interacts with high affinity with the blue/red receptor heteromer and may lead to conformational changes.
See this image and copyright information in PMC

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References

    1. Agnati L. F., Fuxe K., Zoli M., Rondanini C., Ogren S. O. (1982). New vistas on synaptic plasticity: The receptor mosaic hypothesis of the engram. Med. Biol. 60, 183–190. - PubMed
    1. Agnati L. F. L. F., Leo G., Vergoni A.-V. V. A.-V., Martínez E., Hockemeyer J., Lluis C., et al. (2004). Neuroprotective effect of L-DOPA co-administered with the adenosine A2A receptor agonist CGS 21680 in an animal model of Parkinson’s disease. Brain Res. Bull. 64, 155–164. 10.1016/j.brainresbull.2004.06.003 - DOI - PubMed
    1. Alexander S. P., Christopoulos A., Davenport A. P., Kelly E., Mathie A., Peters J. A., et al. (2021). The concise guide to pharmacology 2021/22: G protein-coupled receptors. Br. J. Pharmacol. 178, S27–S156. 10.1111/BPH.15538 - DOI - PubMed
    1. Angulo E., Casadó V., Mallol J., Canela E. I., Viñals F., Ferrer I., et al. (2003). A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation. Brain Pathol. 13, 440–451. 10.1111/j.1750-3639.2003.tb00475.x - DOI - PMC - PubMed
    1. Armentero M. T., Pinna A., Ferré S., Lanciego J. L., Müller C. E., Franco R. (2011). Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacol. Ther. 132, 280–299. 10.1016/j.pharmthera.2011.07.004 - DOI - PMC - PubMed

Grants and funding

This work was supported by grants PID 2020-113430RB-I00 and PID 2021-126600OB-I00 funded by Spanish MCIN/AEI/10.13039/501100011033 and, as appropriate, by “ERDF A way of making Europe,” by the “European Union” or by the “European Union Next- Generation EU/PRTR.” The research group of the University of Barcelona is considered of excellence (grup consolidat #2021 SGR 00304) by the Regional Catalonian Government.

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