RESUMEN
Mu opioid receptor (MOR)-targeting analgesics are efficacious pain treatments, but notorious for their abuse potential. In preclinical animal models, coadministration of traditional kappa opioid receptor (KOR)-targeting agonists with MOR-targeting analgesics can decrease reward and potentiate analgesia. However, traditional KOR-targeting agonists are well known for inducing antitherapeutic side effects (psychotomimesis, depression, anxiety, dysphoria). Recent data suggest that some functionally selective, or biased, KOR-targeting agonists might retain the therapeutic effects of KOR activation without inducing undesirable side effects. Nalfurafine, used safely in Japan since 2009 for uremic pruritus, is one such functionally selective KOR-targeting agonist. Here, we quantify the bias of nalfurafine and several other KOR agonists relative to an unbiased reference standard (U50,488) and show that nalfurafine and EOM-salvinorin-B demonstrate marked G protein-signaling bias. While nalfurafine (0.015 mg/kg) and EOM-salvinorin-B (1 mg/kg) produced spinal antinociception equivalent to 5 mg/kg U50,488, only nalfurafine significantly enhanced the supraspinal analgesic effect of 5 mg/kg morphine. In addition, 0.015 mg/kg nalfurafine did not produce significant conditioned place aversion, yet retained the ability to reduce morphine-induced conditioned place preference in C57BL/6J mice. Nalfurafine and EOM-salvinorin-B each produced robust inhibition of both spontaneous and morphine-stimulated locomotor behavior, suggesting a persistence of sedative effects when coadministered with morphine. Taken together, these findings suggest that nalfurafine produces analgesic augmentation, while also reducing opioid-induced reward with less risk of dysphoria. Thus, adjuvant administration of G protein-biased KOR agonists like nalfurafine may be beneficial in enhancing the therapeutic potential of MOR-targeting analgesics, such as morphine.
Asunto(s)
Analgesia/métodos , Sistemas de Liberación de Medicamentos/métodos , Morfinanos/administración & dosificación , Morfina/administración & dosificación , Dimensión del Dolor/efectos de los fármacos , Receptores Opioides mu/metabolismo , Compuestos de Espiro/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Sinergismo Farmacológico , Femenino , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Dimensión del Dolor/métodos , Distribución Aleatoria , Receptores Opioides kappa/administración & dosificación , Receptores Opioides mu/agonistasRESUMEN
The use of opioids for the treatment of pain, while largely effective, is limited by detrimental side effects including analgesic tolerance, physical dependence, and euphoria, which may lead to opioid abuse. Studies have shown that compounds with a µ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist profile reduce or eliminate some of these side effects including the development of tolerance and dependence. Herein we report the synthesis and pharmacological evaluation of a series of tetrahydroquinoline-based peptidomimetics with substitutions at the C-8 position. Relative to our lead peptidomimetic with no C-8 substitution, this series affords an increase in DOR affinity and provides greater balance in MOR and DOR binding affinities. Moreover, compounds with carbonyl moieties at C-8 display the desired MOR agonist/DOR antagonist profile whereas alkyl substitutions elicit modest DOR agonism. Several compounds in this series produce a robust antinociceptive effect in vivo and show antinociceptive activity for greater than 2 h after intraperitoneal administration in mice.
Asunto(s)
Analgésicos Opioides/síntesis química , Analgésicos Opioides/farmacología , Dolor/tratamiento farmacológico , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , Línea Celular , Cricetulus , Humanos , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Dolor/metabolismo , Unión Proteica , Ratas , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Relación Estructura-ActividadRESUMEN
In an effort to expand the structure-activity relationship (SAR) studies of a series of mixed-efficacy opioid ligands, peptidomimetics that incorporate methoxy and hydroxy groups around a benzyl or 2-methylindanyl pendant on a tetrahydroquinoline (THQ) core of the peptidomimetics were evaluated. Compounds containing a methoxy or hydroxy moiety in the o- or m-positions increased binding affinity to the kappa opioid receptor (KOR), whereas compounds containing methoxy or hydroxy groups in the p-position decreased KOR affinity and reduced or eliminated efficacy at the mu opioid receptor (MOR). The results from a substituted 2-methylindanyl series aligned with the findings from the substituted benzyl series. Our studies culminated in the development of 8c, a mixed-efficacy MOR agonist/KOR agonist with subnanomolar binding affinity for both MOR and KOR.
Asunto(s)
Analgésicos Opioides/química , Peptidomiméticos/química , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Analgésicos Opioides/síntesis química , Analgésicos Opioides/farmacología , Animales , Células CHO , Línea Celular Tumoral , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Encefalina D-Penicilamina (2,5)/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Humanos , Ratones , Naloxona/farmacología , Peptidomiméticos/síntesis química , Peptidomiméticos/farmacología , Unión Proteica , Conformación Proteica , Ratas , Relación Estructura-ActividadRESUMEN
N-Acetylation of the tetrahydroquinoline (THQ) core of a series of µ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands increases DOR affinity, resulting in ligands with balanced MOR and DOR affinities. We report a series of N-substituted THQ analogues that incorporate various carbonyl-containing moieties to maintain DOR affinity and define the steric and electronic requirements of the binding pocket across the opioid receptors. 4h produced in vivo antinociception (ip) for 1 h at 10 mg/kg.
Asunto(s)
Quinolinas/química , Quinolinas/farmacología , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides mu/agonistas , Animales , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Conformación Molecular , Quinolinas/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
In a previously described peptidomimetic series, we reported the development of bifunctional µ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.
Asunto(s)
Analgésicos/síntesis química , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides mu/agonistas , Acetilación , Analgésicos/química , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos C57BL , Dimensión del Dolor/efectos de los fármacos , Ensayo de Unión Radioligante , Receptores Opioides delta/química , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a µ opioid receptor (MOR) agonist, δ opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood-brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance.
Asunto(s)
Analgésicos Opioides/síntesis química , Analgésicos/farmacología , Peptidomiméticos/síntesis química , Fenilpropionatos/síntesis química , Quinolinas/síntesis química , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides mu/agonistas , Analgésicos/síntesis química , Animales , Células CHO , Cricetinae , Tolerancia a Medicamentos/fisiología , Ligandos , Ratones , Fenilpropionatos/farmacología , Quinolinas/farmacología , RatasRESUMEN
This study was designed to determine whether a 5-HT(2C) receptor antagonist could induce a conditioned place preference indicative of reward and/or abuse potential. Here, we present the first evidence that a selective 5-HT(2C) receptor antagonist, 6-chloro-5-ethoxy-N-(pyridin-2-yl)indoline-1-carboxamide hydrochloride (CEPC), can potentiate a low dose (0.5 mg/kg) amphetamine-induced positive conditioned place preference (CPP). CEPC did not produce any CPP given alone at doses of either 2.0 or 4.0 mg/kg, whereas low dose amphetamine alone produced only a slight, but statistically nonsignificant, place preference. These studies suggest that 5-HT(2C) receptor antagonists can indirectly potentiate the rewarding effects of amphetamine, and perhaps other psychostimulants. If the results can be translated to man, putative 5-HT(2C) receptor antagonist treatments for anxiety or depression may enhance or potentiate the rewarding effects of drugs of abuse such as amphetamine, which release dopamine.