26340-10-3Relevant academic research and scientific papers
A novel series of 2,5-substituted tryptamine derivatives as vascular 5HT(1B/1D) receptor antagonists
Moloney, Gerard P.,Robertson, Alan D.,Martin, Graeme R.,MacLennan, Steven,Mathews, Neil,Dodsworth, Susan,Sang, Pang Yih,Knight, Cameron,Glen, Robert
, p. 2347 - 2362 (2007/10/03)
The design, synthesis, and activity of a novel series of 2,5- substituted tryptamine derivatives at vascular 5HT(1B)-like receptors is described. Several important auxiliary binding sites of the 5HT(1B)-like receptor have been proposed following various modifications to the 2- substituent and especially to the methylene- or ethylene-linked 5-side chain. Careful design of new molecules based on a proposed pharmacophoric model of the 5HT(1B)-like receptor has resulted in the discovery of ethyl 3-[2- (dimethylamino)ethyl]-5-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2- carboxylate (40), a highly potent, silent, competitive, and selective antagonist which shows affinity at the vascular 5HT(1B)-like receptors only. Changes to the size of the 2-ester substituent have a significant effect on affinity at the 5HT(1B)-like receptor and other receptors. Prudent placement of the carbonyl substituent in the heterocycle of the 5-side chain is crucial for good affinity and selectivity over the 5HT(2A) and other receptors. Several key structural and electronic features were identified which are crucial for producing antagonism within a tryptamine-based series. An electron deficient indole ring system appears essential in order to achieve antagonism, and this is achieved by the inclusion of electron-withdrawing groups at the 2-position of the indole ring. The molecule displacement within the receptor resulting from the inclusion of the bulky 2-substituents also enhances antagonism as this results in the removal of the Π electon density of the indole ring from the region of the receptor normally occupied by the indole ring of 5HT. There also appears to be a structural requirement on the side chain incorporating the protonatable nitrogen, and this is achieved by the inclusion of the bulky 2-ester group which neighbors the 3-ethylamine side chain.
