A Novel Series of 2,5-Substituted Tryptamine Derivatives as Vascular 5HT<INF>1B/1D</INF> Receptor Antagonists

The design, synthesis, and activity of a novel series of 2,5-substituted tryptamine derivatives at vascular 5HT<INF>1B</INF>-like receptors is described. Several important auxiliary binding sites of the 5HT<INF>1B</INF>-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<INF>1B</INF>-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 (<BO>40</BO>), a highly potent, silent, competitive, and selective antagonist which shows affinity at the vascular 5HT<INF>1B</INF>-like receptors only. Changes to the size of the 2-ester substituent have a significant effect on affinity at the 5HT<INF>1B</INF>-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<INF>2A</INF> 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.