L-654,284 a new potent and selective alpha 2-adrenoceptor antagonist

L-654,284 [(2R, 12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a] quinolizine-2-yl)-N-methyl-2-hydroxyethanesulfonamide) was tested in several in vitro and in vivo models for alpha 2-adrenoceptor antagonist activity and compared to several reference agents. In vitro L-654,284 completed for the binding of 3H-clonidine or 3H-rauwolscine (Ki's 0.8 nM, 1.1 nM) and blocked the presynaptic effects of clonidine in the rat isolated vas deferens (pA2, 9.1). L-654,284 exhibited marked alpha 2-vs. alpha 1-adrenoceptor selectivity in vitro, inhibiting 3H-prazosin binding with a Ki of 110 nM and blocking the effects of methoxamine on the vas deferens with a pA2 of 7.5. In vivo L-654,284 at 22 nmoles/kg i.v. doubled the ED50 of clonidine to produce mydriasis in rats. Given orally, the potency of L-654,284 in this test was reduced by a factor of 5.5. L-654,284 also potently increased cerebrocortical NE turnover in the rat, another in vivo index of alpha 2-adrenoceptor blockade in the central nervous system. In the periphery, L-654,284 demonstrated alpha 2-adrenoceptor selectivity by preferentially blocking the pressor effects of UK 14304 versus those of methoxamine in the pithed rat. Overall, L-654,284 was generally a more potent alpha 2-adrenoceptor antagonist than RX 781094 with comparable alpha 2/alpha 1 selectivity and was several times more potent and alpha 2-selective than WY 26703 or yohimbine. In addition, L-654,284 had better (5-6 times) oral bioavailability than RX 781094 or WY 26703.