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.
Halliday
C A
CA
Department of Neuropharmacology, Glaxo Group Research Ltd, Ware, Hertfordshire.
Jones
B J
BJ
Skingle
M
M
Walsh
D M
DM
Wise
H
H
Tyers
M B
MB
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000700:Analgesics / Q000037:antagonists & inhibitors; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D010883:Piperoxan / Q000031:analogs & derivatives* / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D011810:Quinoxalines / Q000037:antagonists & inhibitors; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D011758:Pyrroles; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D011968:Receptors, Histamine; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D000068438:Brimonidine Tartrate; D010883:Piperoxan; D003000:Clonidine; C065161:fluparoxan; D009638:Norepinephrine