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 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 alpha 1-adrenoceptor agonist phenylephrine with a pKB 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, 0.67-6 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(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain. 5. We conclude that fluparoxan is a highly selective and potent alpha 2-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 beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.

D2 dopamine receptors in rat striatum are homogeneous as revealed by ligand-binding studies.

D2 dopamine receptors in rat striatum have been analysed using the binding of [3H]domperidone. Competition experiments were performed with classical dopamine antagonists and antagonists reported by other workers to discriminate D2 dopamine receptor sub-classes. In all cases competition data conformed to a single binding site interaction so that there is no evidence for heterogeneity of the D2 dopamine receptor.

Why is amitriptyline much weaker than desipramine at decreasing beta-adrenoceptor numbers?

Desipramine is consistently more effective than amitriptyline at causing beta-adrenoceptor down-regulation. Atropine, mepyramine, ketanserin, cyproheptadine and citalopram did not modify this action of desipramine in rats. Therefore inhibition of either muscarinic, histamine-H1, and 5-HT receptors or 5-HT uptake produced by amitriptyline is unlikely to account for its weaker effect on beta-adrenoceptors. A more likely explanation implicates noradrenaline uptake inhibition in vivo since amitriptyline was much weaker than desipramine and only effective after repeated dosing.