Inverse Agonists And Constitutive Activities

Inverse agonists represent an established drug class possessing the property of reducing receptor-mediated constitutive activity of GPCRs. It is the ability of GPCRs to undergo an agonist-independent conversion from the inactive state of the receptor to the activated form that makes them capable of activating G proteins.7879 Arena pharmaceuticals (San Diego, California) developed a technology to identify inverse agonists. Its constitutively activated receptor technology (CART) is based on the generation of receptor mutations that induce constitutive signaling.75 A receptor can be expressed constitutively by changing the amino acid sequences of the interior loops of the receptor so that it does not require a stimulus such as agonist binding to initiate the signaling cascade.

It is important to establish an acceptable level of basal activity by overexpressing the receptor target or altering the molecular structure of an intracellular loop or intracellular portion of the GPCR to generate a CART-activated form of the GPCR. When transfected into mammalian cell lines or Xenopus melanophores, such mutant receptors express the CART-activated form of these receptors at the cell surface and display constitutive activity. Compound screening can be done using this system to identify agonists that increase signaling and antagonists (inverse agonists), which results in a decrease in constitutive activity. Therefore, this technology is not limited to molecules that compete only with the receptor-ligand interactions. Thus, it can facilitate the identification of molecules that modulate the signaling cascade. Also, constitutive activity of receptors can result in an increase in the sensitivity of agonists and the same system could be used to identify agonists and inverse agonists during drug screening. However, its application to HTS is still unproven.

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