RESUMO
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.
Assuntos
Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Triptaminas/farmacologia , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Coelhos , Ensaio Radioligante , Receptor 5-HT1B de Serotonina , Receptor 5-HT1D de Serotonina , Antagonistas da Serotonina/química , Relação Estrutura-Atividade , Triptaminas/química , Vasoconstrição/efeitos dos fármacos , Veias/efeitos dos fármacos , Veias/fisiologiaRESUMO
The synthesis and vascular 5-HT(1B)-like receptor activity of a novel series of substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives are described. Modifications to the 5-ethylene-linked heterocycle and to substituents on the 2-benzylamide side chain have been explored. Several compounds were identified which exhibited affinity at the vascular 5-HT(1B)-like receptor of pK(B) > 7.0, up to 100-fold selectivity over alpha(1)-adrenoceptor affinity and 5-HT(2A) receptor affinity, and which exhibited a favorable pharmacokinetic profile. N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2, 5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxamide (23) was identified as a highly potent, silent (as judged by the inability of angiotensin II to unmask 5-HT(1B)-like receptor-mediated agonist activity in the rabbit femoral artery), and competitive vascular 5-HT(1B)-like receptor antagonist with a plasma elimination half-life of approximately 4 h in dog plasma and with good oral bioavailability. The selectivity of compounds from this series for the vascular 5-HT(1B)-like receptors over other receptor subtypes is discussed as well as a proposed mode of binding to the receptor pharmacophore. It has been proposed that the aromatic ring of the 2, N-benzylcarboxamide group can occupy an aromatic binding site rather than the indole ring. The resulting conformation allows an amine-binding site to be occupied by the ethylamine nitrogen and a hydrogen-bonding site to be occupied by one of the hydantoin carbonyls. The electronic nature of the 2,N-benzylcarboxamide aromatic group as well as the size of substituents on this aromatic group is crucial for producing potent and selective antagonists. The structural requirement on the 3-ethylamine side chain incorporating the protonatable nitrogen is achieved by the bulky 2, N-benzylcarboxamide group and its close proximity to the 3-side chain.
Assuntos
Imidazóis/síntese química , Indóis/síntese química , Músculo Liso Vascular/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Animais , Aorta Torácica/metabolismo , Ligação Competitiva , Córtex Cerebral/metabolismo , Cães , Artéria Femoral/metabolismo , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacocinética , Técnicas In Vitro , Indóis/química , Indóis/metabolismo , Indóis/farmacocinética , Modelos Moleculares , Músculo Liso/metabolismo , Coelhos , Ensaio Radioligante , Ratos , Ratos Wistar , Receptor 5-HT1B de Serotonina , Veia Safena/metabolismo , Antagonistas da Serotonina/química , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacocinética , Relação Estrutura-Atividade , Traqueia/metabolismoRESUMO
A series of 3,4-dihydro-1,3-benzoxazine and 3,4-dihydro-1,3-pyridooxazine derivatives was synthesized, and the hydrolysis of the derivatives was studied with proton nuclear magnetic resonance spectroscopy. The oxazine derivatives underwent various degrees of hydrolysis when H2O was added to dimethyl sulfoxide solutions of the compounds. The rates and extents of decomposition of the oxazine ring systems depended on the electronic effects of substituents within the molecules. Examination of the proton nuclear magnetic resonance spectra that were generated during decomposition of the oxazines and trends in stability of the oxazine derivatives suggest the formation of an intermediate in the hydrolysis mechanism.