The clinical relevance and precise receptor conformational changes that occur, given the structural diversity of compounds with high intrinsic efficacy, remains to be determined. From the Gi‐mediated efficacy ratio, the degree of Gs‐coupling could be predicted. For Gs‐mediated responses to be observed, both a system with high receptor reserve and high agonist intrinsic efficacy were required. ERK1/2‐phosphorylation responses appeared to be Gi‐mediated. Ligands with high intrinsic efficacy (e.g., brimonidine and moxonidine at α2A) stimulated biphasic (Gi‐Gs) concentration responses, however for ligands with low intrinsic efficacy (e.g., naphazoline), responses were monophasic (Gi‐only). Agonist responses to 49 different α‐agonists were studied (CRE‐gene transcription, cAMP, ERK1/2‐phosphorylation and binding affinity) in CHO cells stably expressing the human α2A, α2B or α2C‐adrenoceptor, enabling ligand intrinsic efficacy to be determined (binding K D/Gi‐IC 50). However, despite having the same Gi‐potency in functional assays, some α2‐agonists also stimulate Gs‐responses whilst others do not. Central activation of brain α2A and α2C‐adrenoceptors is the main site for α2‐agonist mediated clinical responses in hypertension, ADHD, muscle spasm and ITU management of sedation, reduction in opiate requirements, nausea and delirium. Α2‐adrenoceptors, (α2A, α2B and α2C‐subtypes), are Gi‐coupled receptors.
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