RESUMEN
A series of 15 novel opioid derivatives were made where the prototypic phenolic-OH group of traditional opioids was replaced by a carboxamido (CONH(2)) group. For 2,6-methano-3-benzazocines and morphinans similar or, in a few instances, enhanced affinity for mu, delta and kappa opioid receptors was observed when the OH-->CONH(2) switch was applied. For 4,5alpha-epoxymorphinans, binding affinities for the corresponding carboxamide derivatives were much lower than the OH partner consistent with our pharmacophore hypothesis concerning carboxamide bioactive conformation. The active metabolite of tramadol and its carboxamide counterpart had comparable affinities for the three receptors.
Asunto(s)
Analgésicos Opioides/síntesis química , Receptores Opioides/metabolismo , Amidas , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Humanos , Unión Proteica , Relación Estructura-Actividad , Tramadol/metabolismoRESUMEN
A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring 'open' derivatives display very high affinity for mu and kappa receptors and much less affinity for delta. The observation that these target compounds have much higher receptor affinity than the corresponding ring 'closed' carboxamides significantly strengthens our underlying pharmacophore hypothesis concerning the bioactive conformation of the carboxamide group.
Asunto(s)
Analgésicos Opioides/síntesis química , Antagonistas de Narcóticos/síntesis química , Receptores Opioides/metabolismo , Analgésicos Opioides/metabolismo , Cristalografía por Rayos X , Furanos/síntesis química , Furanos/metabolismo , Humanos , Ligandos , Naltrexona/síntesis química , Naltrexona/metabolismo , Antagonistas de Narcóticos/metabolismo , Unión Proteica , Receptores Opioides/agonistasRESUMEN
We synthesized a library of Pseudomonas aeruginosa autoinducer analogs with variation targeted to the homoserine lactone (HSL) moiety and discovered a new agonist, 3-oxo-C(12)-(2-aminocyclohexanol), capable of activating LasR as a transcription factor. We reconstructed two sets of focused libraries against the quorum-sensing transcription factors LasR and RhlR, respectively. Opposing the prediction that both proteins should have the same binding site for HSL, it was surprising to find that these two related proteins respond to different structural motifs. This suggests that the HSL binding site differs in these proteins. We also found that subtle structural modifications to the agonists yielded compounds with antagonist activity. We performed a series of assays to show that inhibition of quorum sensing by these antagonists significantly reduced the production of virulence factors and biofilm formation.
Asunto(s)
4-Butirolactona/análogos & derivados , 4-Butirolactona/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Pseudomonas aeruginosa/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transactivadores/antagonistas & inhibidores , 4-Butirolactona/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , Retroalimentación Fisiológica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Sustancias Macromoleculares , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/fisiología , Relación Estructura-Actividad , Factores de Virulencia/antagonistas & inhibidoresRESUMEN
The autoinducer (AI) that initiates the quorum sensing (QS) signaling cascade in Pseudomonas aeruginosa is an acyl-homoserine lactone (acyl-HSL). We initiated a study of the requirements for binding of the AI to its protein effector LasR by synthesizing a library of analogs with the HSL moiety replaced with different amines and alcohols. We tested each compound for both agonist and antagonist activity using a QS-controlled reporter gene assay and found several new agonists and antagonists. A representative antagonist was further tested for its ability to inhibit virulence factors. This data progresses our understanding of the LasR-AI interaction toward the rational design of therapeutic inhibitors of QS.
Asunto(s)
4-Butirolactona/análogos & derivados , Proteínas de Unión al ADN/metabolismo , Biblioteca de Genes , Homoserina/análogos & derivados , Homoserina/metabolismo , Lactonas/metabolismo , Pseudomonas aeruginosa/patogenicidad , Transactivadores/metabolismo , 4-Butirolactona/síntesis química , 4-Butirolactona/farmacología , Aminofenoles/química , Proteínas Bacterianas , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Proteínas de Unión al ADN/química , Diseño de Fármacos , Genes Reporteros/efectos de los fármacos , Técnicas Genéticas , Homoserina/agonistas , Homoserina/antagonistas & inhibidores , Homoserina/síntesis química , Homoserina/genética , Homoserina/farmacología , Lactonas/agonistas , Lactonas/antagonistas & inhibidores , Estructura Molecular , Pseudomonas aeruginosa/metabolismo , Quinolonas/farmacología , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Transactivadores/química , Factores de Virulencia/biosíntesis , Factores de Virulencia/genéticaRESUMEN
8-Position variants of cyclazocine have been made where the phenolic 8-OH was replaced by thioamide, amidine, guanidine, urea and thiourea groups. High affinity for opioid receptors was observed for the 8-CSNH2 and 8-NHCHS analogues indicating that these groups are isosteric with not only the 8-OH but with the previously synthesized 8-CONH2 and 8-NHCHO cyclazocine derivatives.
Asunto(s)
Ciclazocina/química , Ciclazocina/farmacología , Relación Estructura-ActividadRESUMEN
Very high affinity for opioid receptors (e.g., K(i)=0.052nM for mu) has been observed in the rationally designed naltrexone analogue 5. SAR and physical data supports the hypothesis that the 4-OH group of 5 stabilizes the 3-carboxamido group in the putative bioactive conformation.