You are working with a team in a drug company to come up with a drug that decrea

Question

You are working with a team in a drug company to come up with a drug that decreases food intake. Your team has to chosen between two potential G-protein coupled receptor (GCPR) signaling pathways. One pathway when stimulated decreases food intake. A lead receptor agonist compound has been found already that stimulated this GCPR signaling pathway in vitro. Another choice is a pathway that increases food intake when stimulated. It is also regulated by a GPCR. A lead competitive blocker has been identified already for that GPCR that worked in vitro. Our team already knows that both lead compounds acutely affect their target receptors, get into the circulation and bind to their target receptors in the arcuate nucleus, a part of the brain that is involved in satiety regulation but that is also highly fenestrated in terms of the blood brain barrier. The dose needed is pretty comparable. Our team feels that toxicity and bioavailability, cost to synthesize etc., will be similar. However one problem is that there are only enough financial resources to practically pursue one of these avenues. Further expensive preclinical and clinical proof of concept studies are needed to prove that these compounds work in obesity causing weight loss over the long term. All other things being equal, what are the arguments in each case for choosing the pathway where an agonist is use and where an antagonist is used for this purpose? (The arguments would be the same if we were considering another modifiable response such as blood pressure)

Explanation / Answer

There are three main G-protein-mediated signaling pathways, mediated by four sub-classes of G-proteins distinguished from each other by sequence homology (Gs, Gi/o, Gq/11, and G12/13). Each sub-class of G-protein consists of multiple proteins, each the product of multiple genes and/or splice variations that may imbue them with differences ranging from subtle to distinct with regard to signaling properties, but in general they appear reasonably grouped into four classes. Because the signal transducing properties of the various possible combinations do not appear to radically differ from one another, these classes are defined according to the isoform of their -subunit.

While most GPCRs are capable of activating more than one G-subtype, they also show a preference for one subtype over another. When the subtype activated depends on the ligand that is bound to the GPCR, this is called functional selectivity (also known as agonist-directed trafficking, or conformation-specific agonism). However, the binding of any single particular agonist may also initiate activation of multiple different G-proteins, as it may be capable of stabilizing more than one conformation of the GPCR’s GEF domain, even over the course of a single interaction. In addition, a conformation that preferably activates one isoform of G may activate another if the preferred is less available. Furthermore, feedback pathways may result in receptor modifications (e.g.,phosphorylation) that alter the G-protein preference. Regardless of these various nuances, the GPCR’s preferred coupling partner is usually defined according to the G-protein most obviously activated by the endogenous ligand under most physiological and/orexperimental conditions.

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