Time-dependent ligand-receptor binding kinetics and functionality in a heterodimeric receptor model

GPCRs heteromerize both in CNS and non-CNS regions. The cell uses receptor heteromerization to modulate receptor functionality and to provide fine tuning of receptor signaling. In order for pharmacologists to explore these mechanisms for therapeutic purposes, quantitative receptor models are needed. We have developed a timedependent model of the binding kinetics and functionality of a preformed heterodimeric receptor involving two drugs. Two cases were considered: both or only one of the drugs are in excess with respect to the total concentration of the receptor. The latter case can be applied to those situations in which a drug causes unwanted side effects that need to be reduced by decreasing its concentration. The required efficacy can be maintained by the allosteric effects mutually exerted by the two drugs in the two-drug combination system. We discuss this concept assuming that the drug causing unwanted side effects is an opioid and that analgesia is the therapeutic effect. As additional points, allosteric modulation by endogenous compounds and synthetic bivalent ligands was included in the study. Receptor heteromerization offers a mechanistic understanding and quantification of the pharmacological effects elicited by combinations of two drugs at different doses and with different efficacies and cooperativity effects, thus providing a conceptual framework for drug combination therapy.
This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 848068. This publication reflects only the authors’ view and the European Commission is not responsible for any use that may be made of the information it contains. This work is partially supported by the grants PID2020-119136RB-I00, PID-2021-122954NB-I00, PID2022-137708NB-I00 and the Severo Ochoa and María de Maeztu Programs for Centers and Units of Excellence in R&D (CEX2020-001084-M) funded by MCIN/AEI/10.13039/501100011033 and by ERDF “A way of making Europe”, and by the AGAUR grant 2021-SGR-01039. AJO is funded by FPI fellowship (PRE2021-100772) associated to PID2020-119136RB-I00 grant.
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