RESUMEN
The marine dinoflagellate Karenia brevis produces a family of neurotoxins known as brevetoxins. Brevetoxins elicit their effects by binding to and activating voltage-sensitive sodium channels (VSSCs) in cell membranes. K. brevis also produces brevenal, a brevetoxin antagonist, which is able to inhibit and/or negate many of the detrimental effects of brevetoxins. Brevenal binding to VSSCs has yet to be fully characterized, in part due to the difficulty and expense of current techniques. In this study, we have developed a novel fluorescence binding assay for the brevenal binding site. Several fluorescent compounds were conjugated to brevenal to assess their effects on brevenal binding. The assay was validated against the radioligand assay for the brevenal binding site and yielded comparable equilibrium inhibition constants. The fluorescence-based assay was shown to be quicker and far less expensive and did not generate radioactive waste or need facilities for handling radioactive materials. In-depth studies using the brevenal conjugates showed that, while brevenal conjugates do bind to a binding site in the VSSC protein complex, they are not displaced by known VSSC site specific ligands. As such, brevenal elicits its action through a novel mechanism and/or currently unknown receptor site on VSSCs.
Asunto(s)
Encéfalo/efectos de los fármacos , Dinoflagelados/química , Éteres/farmacología , Polímeros/farmacología , Sinaptosomas/efectos de los fármacos , Canales de Sodio Activados por Voltaje/efectos de los fármacos , Animales , Unión Competitiva , Fluorescencia , Ligandos , Estructura Molecular , Neurotoxinas/farmacología , RatasRESUMEN
Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB2 ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB2 agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.
Asunto(s)
Aminopiridinas/química , Morfolinas/química , Piridinas/química , Receptor Cannabinoide CB2/agonistas , Administración Oral , Aminopiridinas/síntesis química , Aminopiridinas/farmacología , Animales , Perros , Humanos , Masculino , Microsomas Hepáticos , Morfolinas/síntesis química , Morfolinas/farmacología , Dolor/tratamiento farmacológico , Unión Proteica , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.
Asunto(s)
Benzamidas/farmacología , Receptor Cannabinoide CB2/efectos de los fármacos , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Benzamidas/uso terapéutico , Dolor/tratamiento farmacológico , RoedoresRESUMEN
For thousands of years mu opioid agonists such as morphine have been utilized for their analgesic properties. Today, morphine and related compounds are still used as a first line therapy in the treatment of moderate to severe pain. However, despite the clear benefits of mu agonists in pain management, severe side effects such as dependence and respiratory depression are associated with use of these drugs. To date, there are only two approved mu opioid antagonists for use in the treatment of these adverse effects, that is, naloxone and naltrexone. However, many other clinical and therapeutic areas have been linked to mu opioid receptor antagonism. These include treatment of opioid induced pruritus of the skin, obesity, and Parkinson-induced tardive dyskinesia. Currently there are two compounds, N-methylnaltrexone and alvimopan, under FDA review as possible treatments for opioid induced bowel dysfunction and postoperative ileus. These compounds are of special interest as they are peripherally restricted. This attribute enables treatment of peripheral side effects induced by opioid agonists without reversal of the centrally mediated analgesia of the agonist. In this article we discuss the structural classes of mu opioid antagonists, their potential clinical applications, and review the relevant patents of the last ten years.
Asunto(s)
Antagonistas de Narcóticos/farmacología , Dolor/fisiopatología , Receptores Opioides mu/antagonistas & inhibidores , Humanos , Antagonistas de Narcóticos/efectos adversos , Antagonistas de Narcóticos/química , Receptores Opioides mu/fisiología , Relación Estructura-ActividadRESUMEN
The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative 3, prototypical mu-opioid antagonist in this series. In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl moiety. The overall modification led to a novel series of fused bicyclic derivatives of the octahydroquinolizine chemical class, conformationally restricted analogue of 3. The constrained analogues 6 and 9 showed high affinity toward the mu-opioid receptor. Compound 6 was found to be a mu-opioid antagonist, whereas the constrained analogue 9 displayed potent mu-agonist activity in vitro. This study provides additional information about the molecular determinants for mu recognition, the structural features affecting ligand binding, and the structure function relationships.
Asunto(s)
Piperidinas/síntesis química , Receptores Opioides mu/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Piperidinas/química , Piperidinas/farmacología , Ensayo de Unión Radioligante , Receptores Opioides mu/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
To better understand structural requirements for a mu ligand of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class to interact with the mu opioid receptor, we have described in the previous article (Le Bourdonnec, B. et al. J. Med. Chem. 2006, 25, 7278-7289) new, constrained analogues of the N-phenethyl derivative 3. One of the active constrained analogues, compound 4, exhibited subnanomolar mu-opioid receptor affinity (K(i) = 0.62 nM) and potent mu-opioid antagonist activity (IC(50) = 0.54 nM). On the basis of structure 4, a new series of mu-opioid receptor antagonists were designed. In these compounds the octahydroquinolizine template of 4 was replaced by an octahydro-1H-pyrido[1,2-a]pyrazine scaffold. The new derivatives were tested for their binding affinities and in vitro functional activity against the cloned human mu-, delta-, and kappa-opioid receptors. From this study, we identified compound 36, which displays high affinity toward the mu-opioid receptor (K(i) = 0.47 nM), potent mu in vitro antagonist activity (IC(50) = 1.8 nM) and improved binding selectivity profile mu/kappa and mu/delta, when compared to 4.
Asunto(s)
Pirazinas/síntesis química , Piridinas/síntesis química , Receptores Opioides mu/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Ligandos , Estructura Molecular , Pirazinas/química , Pirazinas/farmacología , Piridinas/química , Piridinas/farmacología , Ensayo de Unión Radioligante , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides kappa/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Structure-activity relationships at the 2alpha-position of the piperidine ring of the trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine mu-opioid antagonist series were investigated. This study showed that only small linear alkyl groups (methyl, propyl) are tolerated at the 2alpha-position of the piperidine ring of this series.
Asunto(s)
Piperidinas/síntesis química , Piperidinas/farmacología , Receptores Opioides mu/antagonistas & inhibidores , Cristalografía por Rayos X , Modelos Moleculares , Conformación Molecular , Piperidinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
[structure: see text] A model system has been developed to study the synergy between aromatic stacking and hydrogen bonding in the binding of a flavin derivative. The results show that the identity of both the hydrogen bonding and pi-stacking units strongly determine the overall receptor affinity for flavin in both the oxidized and radical anion forms.