Synthesis and Assessment of Fused ß-Carboline Derivatives as Kappa Opioid Receptor Agonists.
ChemMedChem
; 16(12): 1917-1926, 2021 06 17.
Article
en En
| MEDLINE
| ID: mdl-33599108
The synthesis of 5-formyl-6-aryl-6H-indolo[3,2,1-de][1,5] naphthyridine-2-carboxylates by reaction between 1-formyl-9H-ß-carbolines and cinnamaldehydes in the presence of pyrrolidine in water with microwave irradiation is described. Pharmacophoric modification of the formyl group offered several new fused ß-carboline derivatives, which were investigated for their κ-opioid receptor (KOR) agonistic activity. Two compounds 4 a and 4 c produced appreciable agonist activity on KOR with EC50 values of 46±19 and 134±9â
nM, respectively. Moreover, compound-induced KOR signaling studies suggested both compounds to be extremely G-protein-biased agonists. The analgesic effect of 4 a was validated by the increase in tail flick latency in mice in a time-dependent manner, which was completely blocked by the KOR-selective antagonist norBNI. Moreover, unlike U50488, an unbiased full KOR agonist, 4 a did not induce sedation. The docking of 4 a with the human KOR was studied to rationalize the result.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Dolor
/
Carbolinas
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Receptores Opioides kappa
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Analgésicos
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Antagonistas de Narcóticos
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
India