RESUMO
The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic ß-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic ß-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.
Assuntos
Ciproeptadina/toxicidade , Hiperglicemia/induzido quimicamente , Células Secretoras de Insulina/efeitos dos fármacos , Antagonistas de Entorpecentes/toxicidade , Pâncreas/efeitos dos fármacos , Antagonistas da Serotonina/toxicidade , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciproeptadina/análogos & derivados , Diabetes Mellitus Tipo 1/metabolismo , Cães , Epífises/anormalidades , Epífises/metabolismo , Feminino , Ensaios de Triagem em Larga Escala , Hiperglicemia/metabolismo , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Insulinoma/tratamento farmacológico , Insulinoma/metabolismo , Masculino , Camundongos , Osteocondrodisplasias/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Ratos , Ratos Sprague-Dawley , Vacúolos/efeitos dos fármacos , Vacúolos/ultraestruturaRESUMO
Mu-opioid analgesics are a mainstay in the treatment of acute and chronic pain of multiple origins, but their side effects, such as constipation, respiratory depression, and abuse liability, adversely affect patients. The recent demonstration of the up-regulation and membrane targeting of the delta-opioid receptor (DOR) following inflammation and the consequent enhanced therapeutic effect of delta-opioid agonists have enlivened the search for delta-opioid analgesic agents. JNJ-20788560 [9-(8-azabicyclo-[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide] had an affinity of 2.0 nM for DOR (rat brain cortex binding assay) and a naltrindole sensitive DOR potency of 5.6 nM (5'-O-(3-[(35)S]thio)triphosphate assay). The compound had a potency of 7.6 mg/kg p.o. in a rat zymosan radiant heat test and of 13.5 mg/kg p.o. in a rat Complete Freund's adjuvant RH test but was virtually inactive in an uninflamed radiant heat test. In limited studies, tolerance was not observed to the antihyperalgesic or antinociceptive effects of the compound. Unlike ibuprofen, JNJ-20788560 did not produce gastrointestinal (GI) erosion. Although morphine reduced GI motility at all doses tested and reached nearly full effect at the highest dose, JNJ-20788560 did not retard transit at the lowest dose and reached only 11% reduction at the highest dose administered. Unlike morphine, JNJ-20788560 did not exhibit respiratory depression (blood gas analysis), and no withdrawal signs were precipitated by the administration of opioid (mu or delta) antagonists. Coupled with the previously published lack of self-administration behavior of the compound by alfentanil-trained primates, these findings strongly recommend delta-opioid agonists such as JNJ-20788560 for the relief of inflammatory hyperalgesia.
Assuntos
Analgésicos Opioides , Compostos Azabicíclicos/farmacologia , Hiperalgesia/tratamento farmacológico , Receptores Opioides delta/agonistas , Insuficiência Respiratória/induzido quimicamente , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Xantenos/farmacologia , Alfentanil/farmacologia , Animais , Compostos Azabicíclicos/efeitos adversos , Compostos Azabicíclicos/toxicidade , Cricetinae , Tolerância a Medicamentos , Motilidade Gastrointestinal/efeitos dos fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Temperatura Alta , Irritantes/toxicidade , Masculino , Camundongos , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Opioides delta/metabolismo , Insuficiência Respiratória/fisiopatologia , Convulsões/induzido quimicamente , Autoadministração , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Síndrome de Abstinência a Substâncias/psicologia , Xantenos/efeitos adversos , Xantenos/toxicidade , ZimosanRESUMO
Two parallel synthetic methods were developed to explore the structure-activity relationships (SAR) of a series of potent opioid agonists. This series of tropanylidene benzamides proved extremely tolerant of structural variation while maintaining excellent opioid activity. Evaluation of several representative compounds from this series in the mouse hot plate test revealed potent antinociceptive effects upon oral administration.
Assuntos
Analgésicos , Benzamidas , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos/síntese química , Analgésicos/química , Animais , Benzamidas/síntese química , Benzamidas/química , Camundongos , Estrutura Molecular , Medição da Dor/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c, exhibited extremely high affinity for the delta opioid receptor with excellent selectivity versus the micro opioid receptor. They were full agonists at the delta opioid receptor, as assessed by stimulation of GTPgammaS binding, and displayed antinociceptive activity.
Assuntos
Analgésicos Opioides/farmacologia , Benzamidas/farmacologia , Receptores Opioides delta/agonistas , Analgésicos Opioides/química , Benzamidas/química , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Relação Estrutura-AtividadeRESUMO
The tertiary amide delta opioid agonist 2 is a potent antinociceptive agent. Compound 2 was metabolized in vitro and in vivo to secondary amide 3, a potent and selective micro opioid agonist. The SAR of a series of N-alkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides was examined.
Assuntos
Analgésicos/farmacologia , Benzamidas/farmacologia , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos/química , Benzamidas/química , Relação Estrutura-AtividadeRESUMO
The synthesis and structure-activity relationships of a novel series of aroylpyrrole alkylamides as potent selective bradykinin B(2) receptor antagonists are described. Several members of this series display nanomolar affinity at the B(2) receptor and show activity in an animal model of antinociception.