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.
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