152537-06-9Relevant academic research and scientific papers
3-[3-(piperidin-1-yl)propyl]indoles as highly selective h5-HT(1D) receptor agonists
Russell, Michael G. N.,Matassa, Victor G.,Pengilley, Roy R.,Van Niel, Monique B.,Sohal, Bindi,Watt, Alan P.,Hitzel, Laure,Beer, Margaret S.,Stanton, Josephine A.,Broughton, Howard B.,Castro, José L.
, p. 4981 - 5001 (2007/10/03)
Several 5-HT(ID/1B) receptor agonists are now entering the marketplace as treatments for migraine. This paper describes the development of selective h5-HT(1D)receptor agonists as potential antimigraine agents which may produce fewer side effects. A series of 3-[3-(piperidin-1-yl)propyl]indoles has been synthesized which has led to the identification of 80 (L-772,405), a high- affinity h5-HT(1D) receptor full agonist having 170-fold selectivity for h5- HT(1D) receptors over h5-HT(1B) receptors. L-772,405 also shows very good selectivity over a range of other serotonin and nonserotonin receptors and has excellent bioavailability following subcutaneous administration in rats. It therefore constitutes a valuable tool to delineate the role of h5-HT(1D) receptors in migraine. Molecular modeling and physical properties have been utilized to postulate the binding conformation of these compounds in the receptor cavity.
Imidazole, triazole and tetrazole derivatives
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, (2008/06/13)
A class of substituted imidazole, triazole and tetrazole derivatives of formula (I), wherein the broken circle represents two non-adjacent double bonds in any position in the five-membered ring; two, three or four of V,W,X,Y and Z represent nitrogen and the remainder represent carbon provided that, when two of V,W,X,Y and Z represent nitrogen and the remainder represent carbon, then the said nitrogen atoms are in non-adjacent positions within the five-membered ring; E represents a bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms; F represents a group of formula (lI); U represents nitrogen or C--R2 ; B represents oxygen, sulphur or N--R3 ; are selective agonists of 5--HT1 -like receptors and are therefore useful in the treatment of clinical conditions, in particular migraine and associated disorders, for which a selective agonist of these receptors is indicated.
Imidazole, Triazole and tetrazole derivatives
-
, (2008/06/13)
Imidazole, triazole and tetrazole derivatives of formula (I) are selective agonists of 5-HT1 -like receptors and are therefore useful in the treatment of clinical conditions, in particular migraine and associated disorders, for which a selective agonist of these receptors is indicated, wherein the broken circle represents two non-adjacent double bonds in any position in the five-membered ring; two, three or four of V, W, X, Y and Z represent nitrogen and the remainder represent carbon provided that, when two of V, W, X, Y and Z represent nitrogen and the remainder represent carbon, then the said nitrogen atoms are in non-adjacent positions within the five-membered ring; E represents a bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms; F represents a group of formula (a); U represents nitrogen or C--R2 ; B represents oxygen, sulphur or N--R3 ; R1 represents a group of formula (i), (ii) or (iii).
Synthesis and serotonergic activity of N,N-dimethyl-2-[5-(1,2,4-triazol- 1-ylmethyl)-1H-indol-3-yl]ethylamine and analogues: Potent agonists for 5- HT(1D) receptors
Street,Baker,Davey,Guiblin,Jelley,Reeve,Routledge,Sternfeld,Watt,Beer,Middlemiss,Noble,Stanton,Scholey,Hargreaves,Sohal,Graham,Matassa
, p. 1799 - 1810 (2007/10/02)
The synthesis and the 5-HT receptor activity of a novel series of N,N- dimethyltryptamines substituted in the 5-position with an imidazole, triazole, or tetrazole ring are described. The objective of this work was to identify potent and selective 5-HT(1D) receptor agonists with high oral bioavailability and low central nervous system penetration. Compounds have been prepared in which the azole ring is attached through either nitrogen or carbon to the indole. Conjugated and methylene-bridged derivatives have been studied (n = 0 or 1). Substitution of the azole ring has been explored either α or β to the point of attachment to indole. In a series of N-linked azoles (X = N), simple unsubstituted compounds have high affinity and selectivity for 5-HT(1D) receptors. It is proposed that for good affinity and selectivity a hydrogen bond acceptor interaction with the 5-HT(1D) receptor, through a β-nitrogen in the azole ring, is required. In a series of C-linked triazoles and tetrazoles (X = C), optimal affinity and selectivity for the 5-HT(1D) receptor was observed when the azole ring is substituted at the 1-position with a methyl or ethyl group. This study has led to the discovery of the 1,2,4-triazole 10a (MK-462) as a potent and selective 5-HT(1D) receptor agonist which has high oral bioavailability and rapid oral absorption. The in vitro activity and the preliminary pharmacokinetics of compounds in this series are presented.
