Colin F. C. Smith

Selectivity profile of the α2-adrenoceptor antagonist efaroxan in relation to plasma glucose and insulin levels in the rat

The effects of efaroxan (RX 821037A; 2-[2-(2-ethyl-2,3-dihydrobenzofuranyl)]-2-imidazoline HCl) at alpha 1- and alpha 2-adrenoceptors were investigated in isolated tissues, pithed rats and conscious rats. In isolated tissues, efaroxan competitively antagonised the inhibitory effects of p-aminoclonidine in the electrically stimulated (0.1 Hz) rat vas deferens, (pA2 = 8.89) and the contractile effects of phenylephrine on the rat anococcygeus muscle (pA2 = 6.03). Efaroxan had a selectivity ratio (alpha 2/alpha 1) of 724 compared to a value of 182 for idazoxan. In pithed rats, the i.v. doses of efaroxan (mumol/kg) producing 2-fold shifts in dose-response curves for UK-14,304 at prejunctional cardiac alpha 2-adrenoceptors and postjunctional vascular alpha 2-adrenoceptors, and for cirazoline at postjunctional vascular alpha 1-adrenoceptors, were 0.05, 0.13 and 2.96, respectively. In conscious fasted rats, prazosin (5 mg/kg p.o.) increased resting glucose levels and exacerbated the hyperglycaemic effects of UK-14,304 and adrenaline. In contrast, efaroxan (1-5 mg/kg p.o.) had little effect on resting plasma glucose but markedly antagonised the hyperglycaemic actions of UK-14,304 and adrenaline. Efaroxan increased resting plasma insulin levels and markedly potentiated the rise in insulin levels produced by adrenaline; this latter effect was prevented by the co-administration of propranolol. These results demonstrate that efaroxan is a potent and selective alpha 2-adrenoceptor antagonist and provide further support for the involvement of alpha 2-adrenoceptors in glucose homeostasis.

Effect of 1,4-dioxanyl substitution on the adrenergic activity of some standard α-adrenoreceptor agents

Abstract A preliminary communication reported on the pharmacology of the potent partial α2-agonist (2-(1,4-benzodioxan-6-ylamino)-2-imidazoline, a 1,4-dioxan derivative of clonidine. Its degree of agonism/antagonism depended upon the peripheral or central α2-adrenoreceptor system studied. It was of interest to discover whether a similar substitution of the 1,4-dioxan moiety in other standard α-adrenergic agents would similarly produce high affinity compounds of complex pharmacological profile. The same substitution when introduced into guanfacine, fenmetazole and tolazoline resulted in unpredictable changes in profile with a reduction in α-affinity.

Some reactions of 2-azabicycio[2.2.1]hept-5-enes with diphenylketene: preparation of polysubstituted piperidin-2-ones

The azanorbornenes (1) and (3) reacted with diphenylketene to give the 3-azabicyclo[4.3.0]-nonanones (7) and (5) respectively, while the spiro compound (9) afforded the cyclopentenol derivative (10) on reaction with the same ketene.

Comparison of the α-adrenoceptor profiles of clonidine and two oxygenated arylamino imidazolines

The profiles of 2-(3,4-dimethoxyphenylamino)-imidazoline HCl (RX 77171) and 2-[6-(1,4-benzodioxanylamino)]imidazoline maleate (RX 801074) were compared with that of clonidine in isolated tissues and pithed rats. RX 77171 consistently displayed prejunctional α2-adrenoceptor antagonist and postjunctional agonist properties. In contrast, RX 801074 had a complex profile which showed considerable variability between tissues. This variability is highlighted by comparing its effects at the prejunctional α2-adrenoceptors of the isolated vas deferens and guinea-pig ileum; in the former RX 801074 was an agonist whereas only antagonist properties were apparent in the ileum.

Beckmann rearrangements in bicyclo[2.2.1]heptan-2-one oximes

Although Beckmann rearrangement of norcamphor oxime 1 was unsatisfactory, proceeding in poor yield to give a mixture of lactam products, rearrangement of the E/Z oxime 9, or the pure E-isomer 10, upon treatment with methanesulfonyl chloride and triethylamine, gave the lactam 12 in good yield.