A Novel Series of 2,5-Substituted Tryptamine Derivatives as Vascular 5HT_1B/1D Receptor Antagonists

Abstract

The design, synthesis, and activity of a novel series of 2,5-substituted tryptamine derivatives at vascular 5HT1B-like receptors is described. Several important auxiliary binding sites of the 5HT1B-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 5HT1B-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 5HT1B-like receptors only. Changes to the size of the 2-ester substituent have a significant effect on affinity at the 5HT1B-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 5HT2A 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 pi electron 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.

Pyrido[1,2‐a]benzimidazole‐Based Agents Active Against Tuberculosis (TB), Multidrug‐Resistant (MDR) TB and Extensively Drug‐Resistant (XDR) TB

“…The residue was purified by flash chromatography to obtain the desired product. Compounds 2a, b, c, e, h, o, q, r, s, v, w were commercially available, while analytical data for compounds 2d , [24] f , [24] i , [25] m , [24] n , [26] matched the data previously published.…”

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

“…In addition, "selectivity volume" was identified which, if occupied, provided high selectivity for 5-HT 1B/1D over 5-HT 2A receptors. This model, though qualitative, was used to discover a new selective 5-HT 1B/1D partial agonist, with potential use in the treatment of migraine (zolmitriptan, 44), as well as to design new agents with antagonistic properties and to determine their potential binding mode [49]. On the basis of the observation that in the case of tryptamine analogues substitution in 2-position of the indole ring with electron withdrawing groups (45), produced conversion from potent agonists to antagonists, molecular modeling was performed on the respective 2,5-disubstituted tryptamines.…”

“…In order to develop selective 5-HT 1D versus 5-HT 1B receptor agents of different than tryptamine structure, Glennon et al examined a series of 24 2-(benzyl)imidazolines (46,47) and six other related analogues (48)(49)(50)(51)(52)(53) [51]. Two QSAR methods (CoMFA and the Hansch analysis) were applied to characterize the nature of interactions involved in the binding process.…”

Quantitative Phosphokinome Analysis of the Met Pathway Activated by the Invasin Internalin B from Listeria monocytogenes

“…Preparation of 2-{2- (30), and 0.13 g (0.17 ml, 1.00 mmol) of N-ethyldiisopropylamine in 20 ml of propan-2-ol was refluxed for 24 h under an argon atmosphere. The solvent was evaporated under reduced pressure, and the residue was partitioned between 30 ml of water and 30 ml of ethyl acetate.…”