Dissimilar Pharmacological Responses by a New Series of Imidazoline Derivatives at Precoupled and Ligand-Activated α_2A-Adrenoceptor States: Evidence for Effector Pathway-Dependent Differential Antagonism

Abstract

Whereas agonist-directed differential signaling at a single receptor subtype has become an accepted pharmacological concept, distinct behaviors by ligands that are assumed to be antagonists is less documented. The intrinsic activity and capacity of antagonism for a new series of imidazoline-derived adrenergic ligands analogous to dexefaroxan were investigated by measuring two distinct signaling pathways at the recombinant human ␣ 2 -Adrenoceptors (␣ 2 ARs) are cell surface G protein-coupled receptors that bind native catecholamines and couple preferentially to the G i/o family of G proteins (Limbird, 1988). They are widely expressed in both the central and peripheral nervous systems (Eason and Liggett, 1993;Handy et al., 1993;Tavares et al., 1996) and have been shown to participate in a broad spectrum of physiological functions, which include inhibition of neurotransmitter release, regulation of blood pressure (both centrally and within the vasculature), sedation, analgesia, regulation of insulin release and lipolysis, renal function, and multiple behavioral and cognitive functions (Small and Liggett, 2001). The cellular effects of ␣ 2 AR activation include inhibition of adenylate cyclase, activaArticle, publication date, and citation information can be found at

The Concise Guide to PHARMACOLOGY 2013/14: G Protein‐Coupled Receptors

“…Signalling by α 2 ‐adrenoceptors is primarily via G i/o , however the α 2A ‐adrenoceptor also couples to G s . Imidazoline compounds display bias at the α 2A ‐adrenoceptor when assayed by [ 35 S] GTPγS binding compared to inhibition of cAMP accumulation . The noradrenaline reuptake inhibitor desipramine acts directly on the α 2A ‐adrenoceptor, promoting internalisation via recruitment of β‐arrestin without activating G proteins .…”

Structure–activity relationships of inverse agonists for G‐protein‐coupled receptors

“…3) being the only difference that the human a 2A receptor mutant was replaced by WT a 2A receptors. 16 The reduction of 35 S-GTPgS binding by (þ) RX811059 in this test was somewhat lower (38%) than in the previous test (50%). Dexefaroxan acted as a fairly weak inverse agonist reducing basal 35 S-GTPgS binding by 11%, while its 4-methoxy analog RX851062 had the highest reducing effect of the series tested (41%).…”

The Imidazoline Receptor Antagonists Idazoxan and Efaroxan Improve the Spatial and Reference Memory in Rats

“…A new (+) 2-(Ethyl-2,3dihydrobenzofuranyl)-2-imidazoline derivative dexefaroxan, the (+) enantiomer of efaroxan, a potent and selective á2 antagonist, has demonstrated a facilitator effect on the cognitive functions in the passive avoidance test, in rats with scopolamine-induced memory deficit [27][28][29][30]. Moreover, dexefaroxan showed to increase the memorizing performance in passive avoidance test, to improve the spatial memory in Morris swimming test in rats, and to increase the performance of the object recognition, in the specific behavior model in mice [31][32][33][34]. It also improves the cognitive functions in knockout mice with Alzheimer disease [35].…”