The pharmacology of fluparoxan: a selective α 2 ‐adrenoceptor antagonist

1 This paper describes the pharmacology of the novel α 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 α 2 ‐adrenoceptor agonist UK‐14304 with pK B 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 α 1 ‐adrenoceptor agonist phenylephrine with a pK B of 4.45 giving an α 2 :α 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 (ED 50 = 1.4 mg kg −1 , p.o. or 0.5 mg kg −1 , i.v.) and rotarod impairment (ED 50 = 1.1 mg kg −1 p.o. or 1.3 mg kg −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 × 10 −5 m . It displayed weak affinity for 5‐HT 1A (pIC 50 = 5.9) and 5‐HT 1B (pK i = 5.5) binding sites in rat brain. 5 We conclude that fluparoxan is a highly selective and potent α 2 ‐adrenoceptor antagonist. The density of rat brain [ 3 H]‐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 β‐adrenoceptors by fluparoxan is consistent with its antidepressant potential.