Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

Abstract

Chemical and biological strategies have provided evidence for alpha(2)-receptor heterogeneity, to date classified in three different subtypes, alpha(2A), alpha(2B), and alpha(2C). These are widely distributed throughout the body and mediate numerous effects; therefore, the potential therapeutic indications of agonists and antagonists are numerous. Nevertheless, the lack of subtype-selectivity of the well-known compounds represents a major limit for their use. SAR studies may help to design new and more selective drugs.

Functional autoradiography and gene expression analysis applied to the characterization of the α2-adrenergic system in the chicken brain

“…In the same way, while a 2B -adrenoceptor mRNAs in mammals have been reported to be restricted to thalamus and cerebellum (Scheinin et al, 1994), similar amounts of a 2A and a 2B -adrenoceptor subtypes mRNA levels appear in our RT-PCR studies on the chicken brain (a 2A :a 2B ratio close to 1 in all the structures studied). Poor subtype specificity of a 2 -adrenoceptor available ligands (Sallinen et al, 2007;Gentili et al, 2007), or a post-transcriptional regulation of a 2 -adrenoceptor mRNAs, could explain these discrepancies between the pharmacological and real-time PCR studies for a 2 -adrenoceptors. A number of anatomical aspects have to be considered from the results of this study.…”

“…All the assays were carried out simultaneously in rat brain tissue sections to control the smooth running of the experimental conditions. Finally, since a major problem in pharmacologically discriminating a 2 -adrenoceptor subtypes is the lack of subtype-selective ligands (Sallinen et al, 2007;Gentili et al, 2007), the autoradiographic characterization of the anatomical distribution of the different a 2 -adrenoceptor subtypes is very complicated. Instead of this pharmacological approach, we use herein real-time RT-PCR assays in an attempt to describe the distribution of mRNA of the a 2A -, a 2B -, and a 2C -adrenoceptor subtypes in several structures of the chicken brain.…”

Design, synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxy-propyl]-3,3-diphenylpyrrolidin-2-one derivatives with antiarrhythmic, antihypertensive, and α-adrenolytic activity

“…It has also been shown that a 2 -ARs may be localized presynaptically, and act as negative modulators in the release of catecholamine and other neurotransmitters such as acetylcholine, g-aminobutyric acid and nitric oxide [20,21]. In contrast to the a 1 -AR, the post-junctional vascular a 2 -ARs have not yet been established as a target for antihypertension therapy.…”

Analgesia, enhancement of spinal morphine antinociception, and inhibition of tolerance by ultra-low dose of the α2A-adrenoceptor selective antagonist BRL44408

“…Studies using transgenic mice and pharmacological analyses support a primary role of the α 2A -adrenoceptor in pain mediation, although the α 2C subtype may also modulate nociceptive transmission (Gentili et al, 2007). In addition, studies in a mouse line expressing a point mutation in the α 2A -adrenoceptor indicate that the α 2A subtype is the primary mediator of α 2 -adrenergic agonist-induced spinal analgesia, and is necessary for analgesic synergy with opioids (Stone et al, 1997).…”