RESUMO
H(3)R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.
Assuntos
Antagonistas dos Receptores Histamínicos H3/farmacologia , Oxazóis/farmacologia , Receptores Histamínicos H3/química , Animais , Células CHO , Células CACO-2 , Linhagem Celular , Cricetinae , Cricetulus , Desenho de Fármacos , Agonismo Inverso de Drogas , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/química , Humanos , Imidazóis/química , Camundongos , Oxazóis/síntese química , Oxazóis/química , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Histamínicos H3/metabolismo , Relação Estrutura-AtividadeRESUMO
Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.
Assuntos
Agonistas dos Receptores Histamínicos/síntese química , Imidazóis/síntese química , Oxazóis/síntese química , Receptores Histamínicos H3/metabolismo , Animais , Células CHO , Técnicas de Química Combinatória , Cricetinae , Cricetulus , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Cobaias , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Intestinos/efeitos dos fármacos , Intestinos/fisiologia , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Oxazóis/química , Oxazóis/farmacologia , Ligação Proteica , Ensaio Radioligante , Relação Estrutura-AtividadeRESUMO
In this study, the piperidine ring of immepip and its analogues was replaced by a rigid heterocyclic pyridine ring. Many compounds in the series exhibit high affinity and agonist activity at the human histamine H(3) receptor. Particularly, the 4-pyridinyl analogue of immepip (1c, immethridine) is identified as a novel potent and highly selective histamine H(3) receptor agonist (pK(i) = 9.07, pEC(50) = 9.74) with a 300-fold selectivity over the closely related H(4) receptor.
