The in vivo pharmacological profile of a 5‐HT1 receptor agonist, CP‐122, 288, a selective inhibitor of neurogenic inflammation
Authors: Gupta P. , Brown D. , Butler P. , Ellis P. , Grayson K.L. , Land G.C. , Macor J.E. , Robson S.F. , Wythes M.J. , Shepperson N.B. 
Published: July 2012

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.

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 μg kg−1 i.v., P < 0.05). Thus, CP‐122, 288 is of the order of 104 fold more potent than sumatripan.

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.

In a separate series of studies in the anaesthetized rat, CP‐122, 288 (0.003‐3 μg 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 haemodynamic effects.

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.

In the anaesthetized dog, CP‐122, 288 and sumatriptan, at 1–300 μg 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 μg 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.

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.