Molecular pharmacology of alpha2-adrenoceptor agonists (original) (raw)
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Novel α2-adrenoceptor antagonists show selectivity for α2A- and α2B-adrenoceptor subtypes
European Journal of Pharmacology, 1989
Pharmacological characterization of mammalian a2-adrenoceptors in various tissues and species has provided evidence for the existence of two aE-adrenoceptor subtypes. These subtypes can be defined in rat and human tissues by prazosin which is OtEB selective and oxymetazoline which is OtEA selective. In addition to these agents, two types of a2-adrenoceptor antagonists are described which show high affinity and selectivity for the aEg-adrenoceptor and the aEB-adrenoceptor respectively.
Direct labelling of ? 2-adrenoceptors
Naunyn-Schmiedeberg's Archives of Pharmacology, 1985
A radioligand that selectively labels/32-adrenoceptors, 3H-ICI 118,551 (3H-ICI), is introduced. Experiments were performed on guinea-pig tissues. The binding characteristics of 3H-ICI on lung membrane particles are compared with the blocking characteristics of ICI 118,551 against the tracheo-relaxant effects of (-)-noradrenaline, (-)-adrenaline and (+)-fenoterol. Binding to both/31-and /32-adrenoceptors were also performed with 3H-(-)-bupranolol on lung and ventricular myocardium. The binding inhibition characteristics of unlabelled ICI 118,551 on ventricle were compared with its characteristics as antagonist of the positive chronotropic effects of (-)-noradrenaline, (-)-adrenaline and (+)-fenoterol in spontaneously beating right atria.
Different apparent modes of inhibition of α2A-adrenoceptor by α2-adrenoceptor antagonists
European Journal of Pharmacology, 1997
The inhibition of a -adrenoceptor-mediated Ca 2q elevation by a -adrenoceptor antagonists was measured in HEL human 2A 2 Ž erythroleukemia cells. The antagonists could be divided in two classes: those that displayed surmountable inhibition right-shift of the . Ž agonist dose-response curve , and those that displayed different degrees of insurmountable inhibition depression of the maximum signal . and a possible right-shift of the agonist dose-response curve . The degree of surmountability of the inhibition correlated well with the measured antagonist dissociation rates, suggesting that the hypothesis of the antagonist dissociation rate governing the mode of inhibition of fast responses, holds true. HEL cells thus provide a useful model system for the investigation of physiological consequences of different dissociation rates. Also, the dissociation rates of antagonists not available in radiolabelled form can be predicted from the functional data. The data stresses the importance of measurement of kinetic parameters of the drug-receptor interaction in addition to the equilibrium binding constants. q 1997 Elsevier Science B.V.
Naunyn-schmiedebergs Archives of Pharmacology, 1985
A radioligand that selectively labels β 2-adrenoceptors, 3H-ICI 118,551 (3H-ICI), is introduced. Experiments were performed on guinea-pig tissues. The binding characteristics of 3H-ICI on lung membrane particles are compared with the blocking characteristics of ICI 118,551 against the tracheo-relaxant effects of (−)-noradrenaline, (−)-adrenaline and (±)-fenoterol. Binding to both β 1- and β 2-adrenoceptors were also performed with 3H-(−)-bupranolol on lung and ventricular myocardium. The binding inhibition characteristics of unlabelled ICI 118,551 on ventricle were compared with its characteristics as antagonist of the positive chronotropic effects of (−)-noradrenaline, (−)-adrenaline and (±)-fenoterol in spontaneously beating right atria. ICI 118,551 blocked more the relaxant effects of (±)-fenoterol and (−)-adrenaline than those of (−)-noradrenaline on trachea. The positive chronotropic effects of (±)-fenoterol on sinoatrial node were blocked more than those of both (−)-adrenaline and (−)-noradrenaline. A non-linear regression analysis of blocking data with ICI 118,551 according to the model of Lemoine and Kaumann (1983) revelas that both β 1- and β 2-adrenoceptors contribute to the tracheo-relaxant and positive chronotropic effects of agonists. The estimated equilibrium dissociation constants pKB (-log K B=pK B; mol/l) were 7.1 and 9.6 for β 1- and β 2-adrenoceptors, respectively. Tracheal β 2-adrenoceptors contribute 99%, 97% and 7%, sinoatrial β 2-adrenoceptors contribute 76%, 3% and 0% to the fractional stimuli induced by (±)-fenoterol, (−)-adrenaline and (−)-noradrenaline, respectively. 3H-ICI associated to β 2-adrenoceptors of lung membranes with a k on of 0.52 l·nmol−1·min−1 and dissociated with a k off of 0.19 min−1. 3H-ICI bound to lung β 2-adrenoceptors with an equilibrium dissociation constant pKL* of 9.2. Unlabelled ICI 118,551, (−)-bupranolol, (+)-bupranolol, (−)-adrenaline, (−)-noradrenaline and (±)-fenoterol competed with 3H-ICI for lung β 2-adrenoceptors with pK L-values of 9.0, 9.4, 8.1, 5.9, 4.9 and 6.4, respectively. 3H-(−)-bupranolol associated to β-adrenoceptors of lung membranes with a k on 1.2 l·nmol−1·min−1 and dissociated with a k off of 0.26 min−1. 3H-(−)-bupranolol bound to lung β 2-adrenoceptors and to heart β 1-adrenoceptors with a pK L of 9.6 and a pK L of 8.8, respectively. Lung β 2- and β 1-adrenoceptors comprised 3/4 and 1/4 of the β-adrenoceptor population, as estimated independently with 3H-ICI and 3H-(−)-bupranolol; 1/5 of ventricular β-adrenoceptors was β 2, 4/5 β 1. The binding characteristics including stereoselectivity show that 3H-(−)-ICI 118,551 is useful to label nearly exclusively β 2-adrenoceptors in a system containing both β 1- and β 2-adrenoceptors. The affinity for β 2-adrenoceptors of competing ligands can be determined straightforwardly without interference of β 1-adrenoceptors. The low affinity for lung β 2-adrenoceptors but high tracheorelaxant potency of agonists suggest the existence of a large β 1-adrenoceptor reserve.
Agonist channeling of α2-adrenoceptor function
Pharmacochemistry Library, 2002
The a2-adrenergic receptors (a2-ARs) control the function of different organs via central and peripheral effects . Ligands for these receptors have several therapeutic applications includmg anaesthesia and treatment of hypertension and glaucoma. Potential new indications may include obesity and psychiatric disorders. The central effects are thought to mainly be a result of presynaptic mhibition of noradrenaline release. However, a2-ARs are localised at postsynaptic sites as well. The mechanisms involved in the peripheral actions of a2-AR ligands are less well understood. Their effects can be both inhibitory and stimulatory depending on the organ in question [1].
Pharmacology & Therapeutics, 2009
Endogenous, descending noradrenergic fibers convey powerful analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (α 2 ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share similar a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express α 2A AR and α 2C AR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal α 2 ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of these six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal α 2 AR agonists featured.