Actions of terazosin and its enantiomers at subtypes of α- and α2-Adrenoceptorsin vitro

Abstract

Terazosin and its enantiomers, antagonists of alpha 1-adrenoceptors, were studied in radioligand binding and functional assays to determine relative potencies at subtypes of alpha 1- and alpha 2-adrenoceptors in vitro. The racemic compound and its enantiomers showed high and apparently equal affinity for subtypes of alpha 1-adrenoceptors with Kl values in the low nanomolar range, and showed potent antagonism of alpha 1-adrenoceptors in isolated tissues, with the enantiomers approximately equipotent to the racemate at each alpha 1-adrenoceptor subtype. At alpha 2b sites, R(+) terazosin bound less potently than either the S(-) enantiomer or racemate. R(+) terazosin was also less potent than the S(-) enantiomer or the racemate at rat atrial alpha 2B receptors. These agents were not significantly different in their potencies at alpha 2a or alpha 2A sites. Since the high affinity for alpha 2B sites of quinazoline-type alpha-adrenoceptor antagonists has been used to differentiate alpha 2-adrenoceptor subtypes, the low affinity of R(+) terazosin for these sites was unexpected. Because terazosin or its enantiomers are approximately equipotent at alpha 1-adrenoceptor subtypes, the lower potency of R(+) terazosin at alpha 2B receptors indicates a somewhat greater selectivity for alpha 1-compared to alpha 2B adrenoceptor subtypes. The possible pharmacological significance of this observation is discussed.

Pharmacological characterization of A-131701, a novel ?1-adrenoceptor antagonist selective for ?1A- and ?1D-compared to ?1B-adrenoceptors

“…RS 17053 [Ford et al, 1995] is also generally similar, although selectivity was lost using rat submaxillary gland membranes containing α 1A -adrenoceptors (Table 1). In contrast, quinazoline-type α 1 -antagonists (exemplified by prazosin, terazosin, doxazosin, and alfuzosin) did not differentiate strongly among subtypes of α 1 -adrenoceptors (Table 1), although there was generally a somewhat higher affinity for α 1b -adrenoceptors, as has been previously noted Hancock et al, 1995].…”

Prazosin differentially affects extinction of cocaine conditioned place preference on the basis of dose and initial preference

“…For example, previous studies have suggested that prazosin at high doses may have affinity for the α 2 -adrenergic receptor [22], and thus may directly regulate norepinephrine release presynaptically, which also could explain the differential effects of dose outlined here. However, prazosin administration at doses similar to those employed in the current study demonstrates minimal affinity for the α 2 -adrenergic receptor in rat brain [reviewed in 23].…”

“…These experiments, as well as the current study, encourage analyzing behavioral responses in different ways, including examining extinction at different parts of the behavioral scale and in subpopulations that show different levels of initial conditioning, especially regarding measures of CPP [22]. One critical feature of drug dependence in humans is the magnitude of the associations between the rewarding effects of the drug and the cues that predict drug availability.…”

Role of α1-Adrenoceptors of the Locus Coeruleus in Self-Stimulation of the Medial Forebrain Bundle

“…The test drugs were: the a 1 -adrenergic antagonist, terazosin (TER) alone at 3 or 10 nmol/0.5 ml saline in balanced order, the a 1 -adrenergic agonist, phenylephrine (PE), 10 nmol, the combination of TER (10 nmol) plus PE (10 nmol), and the selective a 2 -antagonist, atipamezole (ATI) at 1 nmol. The a 2 -antagonist was used at a lower dose than the a 1 -antagonist because TER's affinity at a 2 -receptors is less than one-tenth its affinity at a 1 -receptors (Hancock et al, 1995). All infusions occurred over 3 min which included 30 s delay before cannula removal.…”