THE PHARMACOLOGY OF FLUPAROXAN - A SELECTIVE ALPHA-2-ADRENOCEPTOR ANTAGONIST

1 This paper describes the pharmacology of the novel alpha-2-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 alpha-2-adrenoceptor agonist UK-14304 with pK(B) values of 7.78 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha-1-adrenoceptor agonist phenylephrine with a pK(B) of 4.45 giving an alpha-2:alpha-1-adrenoceptor selectivity ratio of greater than 2500. 3 In the conscious mouse, fluparoxan (0.2-3.0 mg kg-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 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.676 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4 In specificity stuies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pK(i) = 5.5) binding sites in rat brain. 5 We conclude that fluparoxan is a highly selective and potent alpha-2-adrenceptor antagonist. The density of rat brain [H-3]-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 beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.