• DOI:10.1007/PL00005000
• Corpus ID: 24209214

Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy

@article{NewmanTancredi1997AgonistAO,
  title={Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy},
  author={Adrian Newman-Tancredi and Caroline Conte and Christine Chaput and Laurence Verri{\`e}le and V. Audinot-Bouchez and Sylvia Lochon and Gilbert Lavielle and Mark J. Millan},
  journal={Naunyn-Schmiedeberg's Archives of Pharmacology},
  year={1997},
  volume={355},
  pages={682-688}
}

• A. Newman-Tancredi, C. Conte, +5 authors M. Millan
• Published 15 May 1997
• Biology, Chemistry
• Naunyn-Schmiedeberg's Archives of Pharmacology

The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Affinities (Kis) at this site were determined in competition binding experiments with [3H]-8-OH-DPAT ([3H](±)8-hydroxy-N,N-dipropylaminotetralin), whilst agonist efficacy was measured by stimulation of [35S]-GTPγS (guanylyl-5’-[γ[35S]thio]-triphosphate) binding. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax≥ 90 % relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60 %) and an antagonist, respectively. This suggests that there is no correlation between agonism at 5-HT1A receptors and prophylactic antimigraine action. In contrast, serotonin, dihydroergotamine, sumatriptan, naratriptan and alniditan, which are effective in acute interruption of migraine attacks, each displayed high efficacy (Emax = 100, 100, 92.6, 79.3, 79.1 % respectively) and marked affinity (Ki = 18.7, 0.6, 127, 26.4 and 3.0 nM respectively) at 5-HT1A receptors. EC50 values for agonist stimulation of [35S]-GTPγS binding correlated with respective Ki values at 5-HT1A receptors (r = 0.93) and the stimulation of [35S]-GTPγS binding by these compounds was antagonised by the selective 5-HT1A antagonist WAY100,635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclo-hexanecarboxamide; 100 nM). These data suggest that agonism at 5-HT1A receptors may be involved in some actions of drugs used in acute antimigraine therapy. In comparison with the above compounds, novel ligands targeted at 5-HT1B/1D receptors, such as GR125,743(N-[4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide) and GR127,935 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)-phenyl]-2’-methyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl) -biphenyl-4-carboxamide), only weakly activated [35S]-GTPγS binding (32.4 and 32.1 % efficacy) and displayed moderate affinity at 5-HT1A receptors (Kis 53.1 and 49.8 nM) suggesting that they constitute useful tools to differentiate 5-HT1A and 5-HT1B/1D receptor-mediated actions. In conclusion, the present data indicates that several antimigraine agents exhibit marked 5-HT1A receptor activity and that although this is unlikely to be important for prophylactic action it may be relevant to the ancilliary properties of drugs used for acute migraine treatment.