The pharmacology of fluparoxan: a selective α₂‐adrenoceptor antagonist

Abstract

1 This paper describes the pharmacology of the novel a2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2 In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the a2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the a1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an a2: a1-adrenoceptor selectivity ratio of greater than 2500. 3 In the conscious mouse, fluparoxan (0.2-3.0mgkg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4mgkg-1, p.o. or 0.5mgkg-', i.v.) and rotarod impairment (ED50 = 1.1 mgkg-' p.o. or 1.3 mgkg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4 In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10-s M. It displayed weak affinity for 5-HTlA (pIC50 = 5.9) and 5-HT15 (pKj = 5.5) binding sites in rat brain. 5 We conclude that fluparoxan is a highly selective and potent a2-adrenoceptor antagonist. The density of rat brain [3H]-dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg-1 orally twice daily. The down-regulation of 0-adrenoceptors by fluparoxan is consistent with its antidepressant potential.

Actions of α2 adrenoceptor ligands at α2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for α2A adrenoceptors

“…2) and agreed with previous reports (De Vos et al 1991;Halliday et al 1991;Schoeffter and Hoyer 1991;Arthur et al 1993;Kawai et al 1994). However, the pK i values at rα 2A adrenoceptors correlated poorly with the pK i values at hα 2A receptors (r=0.66; Fig.…”

Third‐generation antidepressants

“…5). 128 Fluparoxan is characterized by a,/al-selective a,-adrenoceptor antagonism, with a potency comparable to that of idazoxan. However, it does not show any agonist activity, presumably because of the absence of an imidazoline moiety.…”

Antagonism of the effects of clonidine by the alpha 2‐adrenoceptor antagonist, fluparoxan.

“…Table 2 shows the statistical analysis of the difference in post-clonidine weighted means between placebo and fluparoxan (except for growth hormone and salivary flow, where it is the ratio of the post-clonidine weighted geometric means). This attenuation occurred following a single dose on day 1 (Figures 1 and 2) and after repeated dosing to predicted steady-state plasma concentrations on day 6 (not shown).…”

“…Fluparoxan (formerly GR50360A), chemical name (±) trans-5-fluoro-2,3,3a,9a-tetrahydro-1 H- [ 1 ,4]-benzodioxide [2,3-C] pyrrole, hydrochloride, hemihydrate is a potent, selective cz2-adrenoceptor antagonist based on both tissue binding and functional in vitro and in vivo studies in animals [1].…”