RESUMEN
The synthesis and biochemical evaluation of novel 1,2,4-oxadiazole-based muscarinic agonists which can readily penetrate into the CNS is reported. Efficacy and binding of these compounds are markedly influenced by the structure and physicochemical properties of the cationic head group. In a series of azabicyclic ligands efficacy and affinity are influenced by the size of the surface area presented to the receptor, at the active site, and the degree of conformational flexibility. The exo-1-azanorbornane 16a represents the optimum arrangement, and this compound is one of the most efficacious and potent muscarinic agonists known. In a series of isoquinuclidine based muscarinic agonists efficacy and affinity are influenced by the geometry between the cationic head.group and hydrogen bond acceptor pharmacophore and steric bulk in the vicinity of the base. The anti configuration represented by 22a is optimal for muscarinic activity. Ligands with pKa below 6.5 show poor binding to the muscarinic receptor as exemplified by the diazabicyclic derivative 42.
Asunto(s)
Oxadiazoles/síntesis química , Parasimpaticomiméticos/síntesis química , Receptores Muscarínicos/efectos de los fármacos , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Técnicas In Vitro , Ligandos , Parasimpaticomiméticos/metabolismo , Ratas , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan 1 (L-732,138) has been identified previously as a potent and selective substance P receptor antagonist. A series of analogs which introduced a 6-membered heterocyclic ring into the backbone of this structure were prepared for evaluation as bioisosteric replacements of the ester linkage of 1. The 2,5-dioxopiperazine 2 had very weak receptor affinity, but 2-oxopiperazine 5 exhibited modest activity. Examination of the conformations accessible to the substituents on these templates led to exploration of the corresponding 5-membered heterocyclic rings. This study culminated in the identification of oxazolidinedione 14 as a suitable ester mimic in terms of the retention of good NK1 binding affinity.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Triptófano/análogos & derivados , Animales , Células CHO/fisiología , Cricetinae , Cristalografía por Rayos X , Ésteres/síntesis química , Ésteres/farmacología , Humanos , Isomerismo , Espectroscopía de Resonancia Magnética/métodos , Conformación Molecular , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Receptores de Neuroquinina-1/metabolismo , Soluciones , Relación Estructura-Actividad , TransfecciónRESUMEN
The major volatile component in the extract of the female sex pheromone gland ofScrobipalpa heliopa was shown to be (E)-3-tridecen-1-ol acetate (V). The identification was based on mass spectral analyses, comparison of retention times with those of synthetic compounds on polar, nonpolar, and liquid crystal gas chromatographic columns and microchemical studies. The latter included hydrolysis and reacetylation, and mass spectral studies of the derivatives formed by epoxidation and methoxymercuration-demercuration. Analysis of gland extracts by gas chromatography linked to electroantennography showed this component to be the only one with significant biological activity, similar to that of the synthetic compound. (E)-3-Tridecenyl acetate (V) attracted male moths to traps in the field while addition of theZ isomer (III) reduced the numbers of moths caught.