1. The aim of the present study was to investigate the in vivo pharmacological profile of
CP-122,288, an
indole-derivative with a conformationally restricted N-methylpyrrolidinyl basic side chain in the C-3 position. This C-3 substituent structurally differentiates
CP-122,288 from the
5-HT1D receptor agonist
sumatriptan, which possesses an N,N-dimethylaminoethyl group. [Formula: see text] 2. When administered prior to electrical stimulation of the trigeminal ganglion,
CP-122,288 (0.3-300 ng kg-1, i.v.) produced a dose-related inhibition of
plasma protein extravasation 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 micrograms kg-1 i.v., P < 0.05). Thus,
CP-122,288 is of the order of 10(4) fold more potent than
sumatriptan. 3. At all doses tested,
CP-122,288 did not inhibit
plasma protein extravasation measured in extracranial tissues such as the lower lip, eyelid, and conjunctiva. 4. In a separate series of studies in the anaesthetized rat,
CP-122,288 (0.003-3 micrograms kg-1 i.v.) produced no change in either heart rate or mean arterial blood pressure, thus demonstrating that doses of
CP-122,288 which inhibit
plasma protein leakage in rat dura, are devoid of hemodynamic effects. 5. Following a 5 min period of electrical stimulation of the trigeminal ganglion, a 20 min period of sustained neurogenically-driven plasma extravasation, occurring in the absence of electrical stimulation, was initiated. By administration of the compound 5 min after completing the phase of electrical stimulation, this protocol permitted the evaluation of the activity of
CP-122,288 on an ongoing and established inflammatory 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 leakage which was consistent with its effects when administered prior to trigeminal ganglion stimulation. 6. In the anaesthetized dog,
CP-122,288 and
sumatriptan, at 1-300 micrograms kg-1, i.v., produced a dose-dependent reduction in carotid arterial blood flow and coronary arterial diameter. These data demonstrate that
sumatriptan inhibits
neurogenic inflammation in the rat (MED, 100 micrograms kg-1, i.v.), and produces vasoconstriction 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. These data demonstrate that in the rat,
CP-122,288 is a highly potent and selective inhibitor of
neurogenic inflammation in intracranial tissues, at doses which are devoid of
vasoconstrictor activity in dog. Potentially,
CP-122,288 may be of use for the acute treatment of
migraine, without the risk of cardiovascular side-effects.