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The pharmacology of RS‐15385‐197, a potent and selective α 2 ‐adrenoceptor antagonist
Author(s) -
Brown C.M.,
MacKin 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.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb12834.x
Subject(s) - prazosin , yohimbine , phenoxybenzamine , chemistry , antagonist , phenylephrine , ileum , stereochemistry , pharmacology , medicine , endocrinology , biology , receptor , biochemistry , blood pressure
1 RS‐15385‐197 ((8a R , 12a S , 13a S )‐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 α 2 ‐adrenoceptors. 2 RS‐15385‐197 had a p K i of 9.45 for α 2 ‐adrenoceptors in the rat cortex (pA 2 in the guinea‐pig ileum of 9.72), whereas the 8aS, 12aR, 13aR enantiomer, RS‐15385‐198, had a p K i of only 6.32 (pA 2 6.47) indicating a high degree of stereoselectivity. The racemate RS‐15385‐196 had a p K i of 9.18. 3 RS‐15385‐197 showed unprecedented α 2 vs. α 1 adrenoceptor selectivity in vitro . In the rat cortex, RS‐15385‐197 had a p K i of 9.45 in displacing [ 3 H]‐yohimbine and 5.29 in displacing [ 3 H]‐prazosin (α 2 /α 1 selectivity ratio in binding experiments > 14000). The compound had a pA 2 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 p K B of 5.9 was obtained against cirazoline‐induced contractions in DSV, whilst a pA 2 of 6.05 was obtained against phenylephrine‐induced contractions in the rabbit aorta (α 2 /α 1 selectivity ratio in functional experiments >4000). 4 RS‐15385‐197 was highly selective for α 2 ‐adrenoceptors over other receptors: the compound showed low affinity for 5‐HT 1A (p K i 6.50) and 5‐HT 1D (p K i 7.00) receptor subtypes, and even lower affinity (p K i < 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 [ 3 H]‐idazoxan, which provides further evidence that these sites are not related to α 2 ‐adrenoceptors. In the DSV, contractile responses to 5‐hydroxytryptamine (5‐HT) were unaffected by a concentration of 1 μ m RS‐15385‐197. 5 RS‐15385‐197 was non‐selective for the α 2A ‐ and α 2B ‐adrenoceptor subtypes in that the p K i for the α 2A ‐adrenoceptor in human platelets was 9.90 and the p K i for the α 2B ‐adrenoceptor in rat neonate lung was 9.70. However, RS‐15385‐197 showed lower affinity for the α 2 ‐adrenoceptor subtype in hamster adipocytes (p K i 8.38). 6 In anaesthetized rats, RS‐15385‐197 was a potent antagonist of the mydriasis response induced by UK‐14,304 or clonidine (AD 50 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 (AD 50 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 α 2 vs. α 1 ‐adrenoceptors was maintained in vivo . 8 RS‐15385‐197 is therefore a very potent, selective, competitive α 2 ‐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 α 2 ‐adrenoceptors.