Alpha-adrenoreceptor reagents. 2. Effects of modification of the 1,4-benzodioxan ring system on alpha-adrenoreceptor activity.
Modification of the 1,4-benzodioxan ring present in RX 781094 has not previously been considered. This paper describes a number of analogues of this ring system, including compounds in which one of the oxygen atoms has been replaced by a methylene group and also those in which the ring size has been changed to give, for example, furan and thiophene derivatives. The dihydrobenzofuranylimidazoline compound 7 is the only analogue possessing presynaptic antagonist potency potency and selectivity comparable to that of 1. In view of this result, a number of derivatives was prepared to determine the structure-activity relationships within this series. Many derivatives, as well as the parent compound 7, were found to possess presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties. Two of the selective presynaptic antagonists, 13 and 14 possess greater potency and selectivity than that possessed by 1. The 5-chloro derivative 25 is twice as potent as after oral administration but only about half as potent when given intravenously.
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis*; D000818:Animals; D004146:Dioxanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D004147:Dioxins / Q000138:chemical synthesis* / Q000494:pharmacology*; D019329:Idazoxan; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D009132:Muscles / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D004147:Dioxins; D007202:Indicators and Reagents; D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; D019329:Idazoxan