SL 84.0418: a novel, potent and selective alpha-2 adrenoceptor antagonist: in vitro pharmacological profile

One novel, potent and selective alpha-2 adrenoceptor antagonist is 2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2- propylpyrrolo[3,2,1-hi]-indole hydrochloride (SL 84.0418). It inhibits with high affinity the radioligand binding to rat cortical alpha-2 adrenoceptors, as well as to human platelet alpha-2 adrenoceptors labeled with [3H]idazoxan (Ki = 7 nM). SL 84.0418 has low affinity for alpha-1 adrenoceptors labeled with [3H]prazosin (Ki = 3.3 microM). In vitro, SL 84.0418 has no alpha agonist properties, whereas it is a potent alpha-2 adrenoceptor antagonist at both pre- and postsynaptic alpha-2 adrenoceptors. In contrast, it possesses low potency as an antagonist at postsynaptic alpha-1 adrenoceptors demonstrating a more than 1000-fold selectivity toward alpha-2 compared with alpha-1 adrenoceptors. In the same tests, the alpha-2 adrenoceptor antagonist idazoxan had a selectivity ratio of 200. SL 84.0418 is the racemic mixture of two enantiomers, SL 86.0715 [(+) enantiomer] and SL 86.0714 [(-) enantiomer]. The alpha-2 adrenoceptor blocking activities reside with SL 86.0715. Similar to idazoxan, SL 84.0418 increases in a concentration-dependent manner the electrically evoked release of [3H]norepinephrine from rat hypothalamic slices through the blockade of the presynaptic inhibitory alpha-2 adrenoceptors. In isolated hamster adipocytes, SL 84.0418 potently antagonizes the inhibition of lipolysis induced by UK 14,304. In addition, SL 84.0418 inhibits epinephrine-induced aggregation of rabbit platelets, effects mediated by postsynaptic alpha-2 adrenoceptors. SL 84.0418 does not inhibit (IC50 > 1,000 nM) radioligand binding to other receptors or recognition sites, nor does it inhibit calcium, sodium or potassium channels.(ABSTRACT TRUNCATED AT 250 WORDS)