The pharmacology of RS‐15385‐197, a potent and selective α2‐adrenoceptor antagonist

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Abstract
1 RS-15385-197 ((8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(methylsulphonyl)-6H-isoquino [2,1-g][1,6]-naphthyridine) was evaluated in a series of in vitro and in vivo tests as an antagonist at α2-adrenoceptors. 2 RS-15385-197 had a pKi of 9.45 for α2-adrenoceptors in the rat cortex (pA2 in the guinea-pig ileum of 9.72), whereas the 8aS, 12aR, 13aR enantiomer, RS-15385-198, had a pKi of only 6.32 (pA2 6.47) indicating a high degree of stereoselectivity. The racemate RS-15385-196 had a pKi of 9.18. 3 RS-15385-197 showed unprecedented α2 vs. α1 adrenoceptor selectivity in vitro. In the rat cortex, RS-15385-197 had a pKi of 9.45 in displacing [3H]-yohimbine and 5.29 in displacing [3H]-prazosin (α2/α1 selectivity ratio in binding experiments > 14000). The compound had a pA2 of 9.72 as a competitive antagonist of the inhibitory effects of UK-14,304 in transmurally-stimulated guinea-pig ileum and 10.0 against BHT-920-induced contractions in dog saphenous vein (DSV); this latter value was unaltered by phenoxybenzamine. An apparent pKB of 5.9 was obtained against cirazoline-induced contractions in DSV, whilst a pA2 of 6.05 was obtained against phenylephrine-induced contractions in the rabbit aorta (α2/α1 selectivity ratio in functional experiments >4000). 4 RS-15385-197 was highly selective for α2-adrenoceptors over other receptors: the compound showed low affinity for 5-HT1A (pKi 6.50) and 5-HT1D (pKi 7.00) receptor subtypes, and even lower affinity (pKi < 5) for other 5-HT receptor subtypes, dopamine receptors, muscarinic cholinoceptors, β-adrenoceptors and dihydropyridine binding sites. RS-15385-197 was devoid of affinity for the non-adrenoceptor imidazoline binding site, labelled by [3H]-idazoxan, which provides further evidence that these sites are not related to α2-adrenoceptors. In the DSV, contractile responses to 5-hydroxytryptamine (5-HT) were unaffected by a concentration of 1 μm RS-15385-197. 5 RS-15385-197 was non-selective for the α2A- and α2B-adrenoceptor subtypes in that the pKi for the α2A-adrenoceptor in human platelets was 9.90 and the pKi for the α2B-adrenoceptor in rat neonate lung was 9.70. However, RS-15385-197 showed lower affinity for the α2-adrenoceptor subtype in hamster adipocytes (pKi 8.38). 6 In anaesthetized rats, RS-15385-197 was a potent antagonist of the mydriasis response induced by UK-14,304 or clonidine (AD50 5 and 7 μg kg−1, i.v., respectively; 96 μg kg−1, p.o.) and of UK-14,304-induced pressor responses in pithed rats (AD50 7 μg kg−1, i.v.); the compound therefore is both centrally and orally active. Even at a high dose (10 mg kg−1, i.v.), RS-15385-197 did not antagonize pressor responses to cirazoline in pithed rats, indicating that the selectivity for α2 vs. α1-adrenoceptors was maintained in vivo. 8 RS-15385-197 is therefore a very potent, selective, competitive α2-adrenoceptor antagonist, both in vitro and in vivo, is orally active and readily penetrates the brain. It will thus be a powerful pharmacological tool for exploring the various physiological roles of α2-adrenoceptors.

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