G-protein coupled receptors antagonists

Engel, S., Skoumbourdis, A.P., Childress, J., Neumann, S., Deschamps, J.R., Thomas, C.J., Colson, A.-0., Costanzi, S., and Gershengorn, M.C. (2008) A virtual screen for diverse ligands discovery of selective G protein-coupled receptor antagonists. Journal of the American Chemical Society, 130, 5115-5123. 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

A neutral antagonist binds equally to both active and inactive states of a G-protein-coupled receptor, regardless of activation state, and therefore blocks the actions of agonists and inverse agonists alike. 

An interesting development in this area is the possibility that there could be an endogenous ligand, for these receptors 5-HT-moduline. This is a tetrapeptide that is released from neurons and is claimed to be the first allosteric modulator of a G protein-coupled receptor to be identified so far. Functionally, 5-HT-moduline behaves like a 5-HTib antagonist and so increases terminal release of 5-HT (Massot et al. 1998) and it is thought that this could be an important step in maintaining a sustained increase in release of 5-HT during stress. 

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Keywords Activation agonist antagonist desensitization efficacy G protein-coupled receptor pharmacogenetics potency single nucleotide polymorphism variant. 

Buck, E., Wells, J.A. Disulfide trapping to localize small-molecule agonists and antagonists for a G protein-coupled receptor. Proc. Natl Acad. Sci. USA 2005, 102, 2719-2724. 

It is universally accepted that the action of opioids is mediated by specific receptors. It is presumed that several types of opioid receptors exist p, k, 5, and a. A few of these are in turn subdivided into subtypes. It has been found that opioid receptors are seven transmembrane G-protein-coupled receptors that are localized in the membranous part of the synaptosomal head it has also been found that they are glycoproteins. They are prone to conformational changes in certain situations, which is essential for their selective binding with agonists or antagonists. 

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