THE IN-VIVO PHARMACOLOGICAL PROFILE OF A 5-HT1 RECEPTOR AGONIST, CP-122,288, A SELECTIVE INHIBITOR OF NEUROGENIC INFLAMMATION

1 The aim of the present study was to investigate the in vivo pharmaco logical profile of CP-122,288, an indole-derivative with a conformatio nally restricted N-methylpyrrolidinyl basic side chain in the C-3 posi tion. This C-3 substituent structurally differentiates CP-122,288 from the 5-HT1D receptor agonist sumatriptan, which possesses an N,N-dimet hylaminoethyl group. [GRAPHICS] 2 When administered prior to electrica l stimulation of the trigeminal ganglion, CP-122,288 (0.3-300 ng kg(-1 ), i.v.) produced a dose-related inhibition of plasma protein extravas ation in rat dura mater (minimum effective dose, MED, 3 ng kg(-1) i.v. , P < 0.05; maximal inhibition of plasma extravasation at 30 ng kg(-1) i.v., P < 0.01). Sumatriptan produced a similar inhibition of plasma leakage in the dura, but at much higher dose levels (MED, 100 mu g kg( -1) i.v., P < 0.05). Thus, CP-122,288 is of the order of 10(4) fold mo re potent than sumatripan. 3 At all doses tested, CP-122,288 did not i nhibit plasma protein extravasation measured in extracranial tissues s uch as the lower lip, eyelid, and conjunctiva. 4 In a separate series of studies in the anaesthetized rat, CP-122,288 (0.003-3 mu g kg(-1) i .v.) produced no change in either heart rate or mean arterial blood pr essure, thus demonstrating that doses of CP-122,288 which inhibit plas ma protein leakage in rat dura, are devoid of haemodynamic effects. 5 Following a 5 min period of electrical stimulation of the trigeminal g anglion, a 20 min period of sustained neurogenically-driven plasma ext ravasation, occurring in the absence of electrical stimulation, was in itiated. By administration of the compound 5 min after completing the phase of electrical stimulation, this protocol permitted the evaluatio n of the activity of CP-122,288 on an ongoing and established inflamma tory event. CP-122,288 (30 and 300 ng kg(-1), i.v., P < 0.01 and P < 0 .05, respectively) produced a complete inhibition of plasma protein le akage which was consistent with its effects when administered prior to trigeminal ganglion stimulation. 6 In the anaesthetized dog, CP-122,2 88 and sumatriptan, at 1-300 mu g kg(-1), i.v., produced a dose-depend ent reduction in carotid arterial blood flow and coronary arterial dia meter. These data demonstrate that sumatriptan inhibits neurogenic inf lammation in the rat (MED, 100 mu g kg(-1), i.v.), and produces vasoco nstriction in the dog, over a similar dose-range. Interestingly, doses of CP-122,288 that inhibit neurogenic inflammation in rat dura mater (0.3-300 ng kg(-1)) were demonstrated to be devoid of vasoconstrictor activity in either the carotid or coronary vascular beds of dog. 7 The se data demonstrate that in the rat, CP-122,288 is a highly potent and selective inhibitor of neurogenic inflammation in intracranial tissue s, at doses which are devoid of vasoconstrictor activity in dog. Poten tially, CP-122,288 may be of use for the acute treatment of migraine, without the risk of cardiovascular side-effects.