title: 2-Alkyl analogue of idazoxan (RX 781094) with enhanced antagonist potency and selectivity at central alpha 2-adrenoceptors in the rat.
abstract: Four 2-alkyl (methyl, ethyl, n-propyl and isopropenyl) analogues of idazoxan (RX 781094) have been synthesized and assessed in terms of their central alpha 2/alpha 1-adrenoceptor selectivity and alpha 2-adrenoceptor antagonist potency using both in vitro and in vivo tests in the rat. In cortical binding assays using [3H]-idazoxan and [3H]-prazosin, idazoxan had a 5 times greater alpha 2/alpha 1-selectivity than yohimbine. The 2-alkyl substituted analogues all showed improved selectivity, being between 17 and 29 times more selective than yohimbine for [3H]-idazoxan binding sites. In terms of central antagonist potency in vivo, the most favourable substitutions were 2-ethyl (RX 811033) and 2-n-propyl (RX 811054). Compared with yohimbine, these analogues were, respectively, 36 and 18 times more potent intravenously and 5 and 7.5 times more potent orally in their antagonism of guanoxabenz-induced mydriasis in the pentobarbitone-anaesthetized rat. All the analogues had a duration of action similar to that of idazoxan, which was significantly shorter than that of yohimbine. The results indicate that introduction of alkyl groups in the 2-position of idazoxan greatly increases the alpha 2/alpha 1-adrenoceptor selectivity as measured in binding studies. Improved alpha 2-adrenoceptor affinity and antagonist potency were particularly associated with the 2-ethyl and 2-n-propyl analogues.
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004146:Dioxanes / Q000378:metabolism / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology*; D019329:Idazoxan; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D011807:Quinolizines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D004147:Dioxins; D011807:Quinolizines; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; C038538:Wy 26703; D011224:Prazosin; D019329:Idazoxan