Pharmacological characterization of almotriptan:: an indolic 5-HT receptor agonist for the treatment of migraine

被引:39
作者
Bou, J [1 ]
Domènech, T [1 ]
Puig, J [1 ]
Heredia, A [1 ]
Gras, J [1 ]
Fernández-Forner, D [1 ]
Beleta, J [1 ]
Palacios, JM [1 ]
机构
[1] Almirall Prodesfarma, Res Ctr, Barcelona 08024, Spain
关键词
5-HT receptor; cAMP accumulation; vasoconstriction;
D O I
10.1016/S0014-2999(00)00876-1
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Almotriptan (3-[2-(dimethylamino)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl)-1 H-indole) has been studied in several models predictive of activity and selectivity at 5-HT receptors. Almotriptan showed low nanomolar affinity for the 5-HT1B and 5-HT1D receptors in several species, including the human, while affinity for 5-HT receptors other than 5-HT1B/1D was clearly less. Affinity for 5-HT7 and 5-HT1A receptors was approximately 40 and 60 times lower than that for 5-HT1B/1D receptors, respectively. Almotriptan did not exhibit significant affinity for several non-5-HT receptors studied up to 100 muM. Almotriptan inhibited forskolin-stimulated cyclic AMP accumulation in HeLa cells transfected with 5-HT1B or 5-HT1D human receptors. In this model, almotriptan had the same efficacy as serotonin and an affinity in the low nanomolar range. It induced vasoconstriction in several vessels in which it was compared with sumatriptan. In isolated dog saphenous veins, almotriptan elicited concentration-dependent contractions with an EC50 of 394 nM. In both these systems, almotriptan behaved as a full agonist. Infusion of almotriptan into the porcine meningeal vasculature induced vasoconstriction. In contrast, in the pig renal and rabbit mesenteric arteries, it had a very low maximal efficacy even at 100 muM, with similar results obtained in the rabbit renal artery. The results suggest that almotriptan is a potent and selective 5-HT1B/1D receptor agonist, with selectivity for the cranial vasculature as compared with peripheral vessels. (C) 2000 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:33 / 41
页数:9
相关论文
共 45 条
[1]  
AHARONY D, 1993, MOL PHARMACOL, V44, P356
[2]   RECEPTOR-BINDING AT 2 DIFFERENT TEMPERATURES TO DISCRIMINATE AGONIST AND ANTAGONIST BEHAVIOR OF ADENOSINE-A1-RECEPTOR LIGANDS IN RAT-BRAIN [J].
BOREA, PA ;
VARANI, K ;
MALAGUTI, V ;
GILLI, G .
JOURNAL OF PHARMACY AND PHARMACOLOGY, 1991, 43 (12) :866-868
[3]  
BOTTGER M, 1991, OXIDOREDUCTION PLASM, V2, P207
[4]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[5]   HOMOGENEOUS 5-HT1D RECOGNITION SITES IN THE HUMAN SUBSTANTIA-NIGRA IDENTIFIED WITH A NEW IODINATED RADIOLIGAND [J].
BRUINVELS, AT ;
LANDWEHRMEYER, B ;
WAEBER, C ;
PALACIOS, JM ;
HOYER, D .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1991, 202 (01) :89-91
[6]   CHARACTERIZATION OF 3 NONPEPTIDE ENDOTHELIN RECEPTOR LIGANDS USING HUMAN CLONED ET(A)-RECEPTOR AND ET(B)-RECEPTOR [J].
BUCHAN, KW ;
ALLDUS, C ;
CHRISTODOULOU, C ;
CLARK, KL ;
DYKES, CW ;
SUMNER, MJ ;
WALLACE, DM ;
WHITE, DG ;
WATTS, IS .
BRITISH JOURNAL OF PHARMACOLOGY, 1994, 112 (04) :1251-1257
[7]  
CABARROCAS X, 1998, 40 ANN SCI M AM ASS
[8]   OPIATE RECEPTOR-BINDING AFFECTED DIFFERENTIALLY BY OPIATES AND OPIOID PEPTIDES [J].
CHILDERS, SR ;
CREESE, I ;
SNOWMAN, AM ;
SNYDER, SH .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1979, 55 (01) :11-18
[9]   [H-3] DUP-753, A HIGHLY POTENT AND SPECIFIC RADIOLIGAND FOR THE ANGIOTENSIN-II-1 RECEPTOR SUBTYPE [J].
CHIU, AT ;
MCCALL, DE ;
ALDRICH, PE ;
TIMMERMANS, PBMWM .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1990, 172 (03) :1195-1202
[10]   Migraine therapy: relationship between serotonergic contractile receptors in canine and rabbit saphenous veins to human cerebral and coronary arteries [J].
Cohen, ML ;
Johnson, KW ;
Schenck, KW ;
Phebus, LA .
CEPHALALGIA, 1997, 17 (06) :631-638