.alpha.-Adrenoceptor reagents. 2. Effects of modification of the 1,4-benzodioxan ring system on .alpha.-adrenoreceptor activity

Abstract

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paper describes a number of analogues of this ring system, including compounds in which one of the oxygen atoms has been replaced by a methylene group and also those in which the ring size has been changed to give, for example, furan and thiophene derivatives.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.

The effects of idazoxan and other α2‐adrenoceptor antagonists on food and water intake in the rat

“…Berridge; unpublished observations). In addition, both idazoxan and also the c2-antagonist efaroxan (Chapleo et al, 1984), produce diuresis in man (unpublished clinical observations). Again the mechanism for this response is unknown but it is unlikely to involve indirect activation of fl-adrenoceptors since the 0-agonist isoprenaline reduces urine flow in rats (Lehr et al, 1967).…”

[3H]2-(2-Benzofuranyl)-2-imidazoline, a highly selective radioligand for I2-imidazoline receptor binding sites Studies in rabbit kidney membranes

“…In earlier in vivo studies, 2-BFI demonstrated very weak antagonism at presynaptic a 2 -ARs in mouse vas deferens and weak agonist activity at postsynaptic a 1 -ARs in rat anococcygeus muscle preparations (Chapleo et al 1984). 2-BFI also displayed very low agonist activity compared to clonidine at postsynaptic a 2 -ARs (Chapleo et al 1984). Recent studies, however, demonstrate that 2-BFI has a higher selectivity than idazoxan or cirazoline for I 2 -RBS over a 2 -ARs labelled by [ 3 H]idazoxan and [ 3 H]RX821002, respectively (Carpéné et al 1995) and 2-BFI has recently become available in a tritium-labelled form (Lione et al 1996).…”

“…2(2-Benzofuranyl)-2-imidazoline (2-BFI; RX801077), has been recently characterised as an I-RBS selective drug (up to 2,800-fold higher affinity at I 2 -RBS than a 2 -ARs; Carpéné et al 1995;Hudson et al 1995). In earlier in vivo studies, 2-BFI demonstrated very weak antagonism at presynaptic a 2 -ARs in mouse vas deferens and weak agonist activity at postsynaptic a 1 -ARs in rat anococcygeus muscle preparations (Chapleo et al 1984). 2-BFI also displayed very low agonist activity compared to clonidine at postsynaptic a 2 -ARs (Chapleo et al 1984).…”

Antagonists that differentiate between ?2A- and ?2D-adrenoceptors

“…31 of Stillings et al 1985;O'Rourke et al 1994a) and efaroxan (compound no. 13 of Chapleo et al 1984;Langin et al 1990), and the benzoxathian derivative benoxathian (Melchiorre et al 1984;Michel et al 1989). The receptors studied were the ~2A-autoreceptors at the noradrenergic axons of the rabbit brain cortex (Trendelenburg et al 1993) and the c~2D-autoreceptors at the noradrenergic axons of the guinea-pig brain cortex .…”