The pharmacology of RS‐15385‐197, a potent and selective α2‐adrenoceptor antagonist
Authors: Brown C.M. , MacKinnon A.C. , Redfern W.S. , Hicks P.E. , Kilpatrick A.T. , Small C. , Ramcharan M. , Clague R.U. , Clark R.D. , MacFarlane C.B. , Spedding M. 
Published: July 2012

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.

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.

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).

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.

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).

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.

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.