Preclinical Neuropharmacology of Naratriptan

Abstract

The basic CNS neuropharmacology of naratriptan is reviewed here. Naratriptan is a second-generation triptan antimigraine drug, developed at a time when CNS activity was thought not to be relevant to its therapeutic effect in migraine. It was, however, developed to be a more lipid-soluble, more readily absorbed and less readily metabolized variant on preexisting triptans and these variations conferred on it a higher CNS profile. Naratriptan is a 5-HT(1B/1D) receptor agonist with a highly selective action on migraine pain and nausea, without significant effect on other pain or even other trigeminal pain. Probable sites of therapeutic action of naratriptan include any or all of: the cranial vasculature; the peripheral terminations of trigeminovascular sensory nerves; the first-order synapses of the trigeminovascular sensory system; the descending pain control system; and the nuclei of the thalamus. Naratriptan may prevent painful dilatation of intracranial vessels or reverse such painful dilatation. Naratriptan can prevent the release of sensory peptides and inhibit painful neurogenic vasodilatation of intracranial blood vessels. At the first order synapse of the trigeminal sensory system, naratriptan can selectively suppress neurotransmission from sensory fibers from dural and vascular tissue, while sparing transmission from other trigeminal fibers, probably through inhibition of neuropeptide transmitter release. In the periaqueductal gray matter and in the nucleus raphe magnus, naratriptan selectively activates inhibitory neurons which project to the trigeminal nucleus and spinal cord and which exert inhibitory influences on trigeminovascular sensory input. Naratriptan has also a therapeutic effect on the nausea of migraine, possibly exerting its action at the level of the nucleus tractus solitarius via the same mechanisms by which it inhibits trigeminovascular nociceptive input. The incidence of naratriptan-induced adverse effects in the CNS is low and it is not an analgesic for pain other than that of vascular headache. In patients receiving selective serotonin uptake inhibitors (SSRIs) naratriptan may cause serotonin syndrome-like behavioral side effects. The mechanism of action involved in the production of behavioral and other CNS side effects of naratriptan is unknown.

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

“…(57)) [512][513][514][515][516][517][518][519]. Sumatriptan was the first of these compounds to be developed, and offered improved efficacy and tolerability over ergotderived compounds [520].…”

Triptans, Serotonin Agonists, and Serotonin Syndrome (Serotonin Toxicity): A Review

“…Triptans were not initially synthesized for CNS penetration, which was thought undesirable. Receptor data on most of them are sparse 53 . Measured HCR affinities at 5‐HT2A receptors are thousands of times less than at 1D (Kis of ∼10 thousand nM vs ∼10 nM), and for 1A receptors hundreds of times less 54‐56 .…”

The Lack of Peripheral Pathology in Migraine Headache

“…Why do some people have aura without pain and others pain without aura? Why are those triptans with higher theoretical octanol‐water partition coefficients (Po, related to better brain penetrance) more effective than those with lower Po's? 4 Migraine pain is unique in its apparent source, its lack of apparent pathological cause, the variable nature both of the factors that trigger it and of the drugs that prevent or relieve it, its intensity, its periodicity and its response to specific pharmacological agents. These are features unique to migraine.…”