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Adrenoceptors: Classification and Distribution
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Further roles for imidazoline receptors are now emerging. Imidazolines, such as efaroxan (see Table 5.2), enhance the rate of insulin secretion from the islets of Langerhans, possibly through I2 receptors (Chan et al. 1994). Clonidine and the selective I1 imidazoline agonist, moxonidine (see Table 4.3), inhibit gastric acid secretion and reduce ethanol-induced gastric mucosal injury (Glavin & Smyth 1995). Moxonidine also induces sodium and water excretion when given centrally (Penner & Smyth 1994). However, peripheral administration of the α2-agonists, rilmenidine (I1) and guanabenz (I2), increased blood pressure and urine excretion via α2-adrenoceptors (Evans & Anderson 1995).
Responsiveness of α2-adrenoceptor/I1-imidazoline receptor in the rostral ventrolateral medulla to cardiovascular regulation is enhanced in conscious spontaneously hypertensive rat
Published in Clinical and Experimental Hypertension, 2019
Masanobu Yamazato, Minori Nakamoto, Atsushi Sakima, Yoriko Yamazato, Shuichi Takishita, Yusuke Ohya
Either α2-adrenoceptors (20) or non-adrenergic imidazoline binding site (hypothetical I1-imidazoline receptors) (21) or both (22) may mediate the sympathoinhibitory effect of clonidine and related drugs in the RVLM. However, previous studies (23–25) suggest that the functional dominance of imidazoline receptors in the RVLM I1-receptors has never been cloned or convincingly identified. In contrast, the importance of central α2A-receptors in the action of clonidine was studied in genetically engineered mice expressing mutated α2A-adrenoceptor, but with intact α2B and α2C adrenoceptor subtypes of α2-adrenoceptor; the study showed that impaired α2A-adrenoceptor is sufficient to eliminate the hypotensive effect of clonidine (26). In the present study, the hypotensive and bradycardic effects of clonidine microinjection into RVLM were abolished in WKY rats and significantly attenuated in SHRs with co-injection of 2-methoxyidazoxan—a selective α2-adrenoceptor antagonist. The findings of the present study in conjunction with previous reports (9,26,27) indicate that α2-adrenoceptors in the RVLM contribute to the action of clonidine in the RVLM. Furthermore, the same dose of efaroxan [an α2-antagonist with 40-fold greater affinity for I1-imidazoline receptors (28)] attenuated clonidine-induced hypotension. This finding indicates that I1-imidazoline receptors in the RVLM also contribute to the action of clonidine in the RVLM.
The latest automated docking technologies for novel drug discovery
Published in Expert Opinion on Drug Discovery, 2021
It is common in literature the use of reverse docking to detect adverse drug reactions and drug toxicities. For instance, Eric et al [55] performed a reverse docking protocol to investigate the cytotoxic activity of a set of 16 previously synthesized arylaminopyridine and arylaminoquinoline derivatives. Among the included potential targets explored in their investigation, they proposed that protein kinases (PKs) and topoisomerase I are responsible of the cytotoxic effect of aminopyridines. In other work, Fan et al [56] used network pharmacology and reverse docking to investigate the adverse effects of the drug torcetrapib related to increase of mortality and cardiac events. Authors docked torcetrapib into a set of protein targets based on enriched signaling pathways and found four potential off-targets: platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR), IL-2 Receptor, and ErbB1 tyrosine kinase. In other work, Ma et al [57] applied a reverse docking protocol to predict the toxicity-related target proteins for melamine and cyanuric acid (a melamine metabolite). Authors identified four target proteins related to the molecular basis of the nephrotoxicity induced by melamine. In a more recent work, Djikic et al [58] performed a reverse docking protocol on 107 class A GPCRs, using 63 imidazoline ligands and their decoys, to investigate possible off-target effects of these ligands. Authors verified their in silico results by evaluating the antagonistic activity on α2-adrenoceptors of ligands with high and low scores. They found potential off-target GPCRs for efaroxan and idazoxan and proposed mechanisms to understand side effects of these drugs.