Almotriptan

Almotriptan was first marketed in Spain as a new medicine against acute attacks of migraine. It is the fifth agent belonging to the “triptan” class to be launched after sumatriptan, naratriptan, zolmitriptan and rizatriptan. This close structural analog of sumatriptan can be prepared in six steps from 4-nitrobenzylsulfonyl chloride with a Fischer indole synthesis as the key step. Almotriptan acts as a dual 5-HT_1D/1B agonist with a 35 to 51-fold selectivity versus 5-HT_1A and 5-HT₇ receptors respectively as well as having insignificant affinity for the most relevant nonserotonergic receptors (K1＞1μM). Its agonistic effect on 5-HT,n receptors of trigeminal sensory neurons turns off neurogenic inflammation by inhibiting the release of neuropeptides such as calcitonin gene-related peptide, neurokinin A and substance P. Concomitantly, its action on the 5-HT_1B receptors in meningeal arteries relieves the vasodilatation of these vessels associated with migraine attacks. Almotriptan causes selective concentration-dependent vasoconstriction of human meningeal and temporal arteries (with EC₅₀ of 0.03 and 0.7 μM) compared to basilar (EC₅₀ = 3.5 μM) and pulmonary arteries (EC₅₀＞10μM) or rabbit mesenteric and renal arteries (EC₅₀＞100 μM). Although it is predominantly cleared by the kidneys as unchanged drug (45%) or transformed into inactive metabolites by monoamine oxidase A (MAO-A) and CYP3A4 enzymes in the liver, almotriptan has the highest oral bioavailability (70%) of the triptans and has a half-life of 3.5 h. The therapeutic dose of 12.5 mg is well tolerated, shows a rapid onset of action (30 min) and low recurrence rate compared to sumatriptan.