RESUMEN
Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OCH3 group with phenyl (4), methyl (5), or 3'-furanyl [6 (SC13)] substituents demonstrated partial agonism with a lower efficacy than DAMGO or morphine in heterologous G-protein assays and synaptic physiology. In assays limiting MOR reserve, the G-protein efficacy of all three was comparable to buprenorphine. 6 (SC13) showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning in mice. These results suggest the possibility of activating MOR minimally (G-protein Emax ≈ 10%) in cell lines while yet attaining maximal antinociception in vivo with reduced opioid liabilities.
Asunto(s)
Analgésicos Opioides/farmacología , Receptores Opioides mu/agonistas , Alcaloides de Triptamina Secologanina/farmacología , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/síntesis química , Analgésicos Opioides/metabolismo , Animales , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Ratas Sprague-Dawley , Receptores Opioides mu/metabolismo , Alcaloides de Triptamina Secologanina/efectos adversos , Alcaloides de Triptamina Secologanina/síntesis química , Alcaloides de Triptamina Secologanina/metabolismo , Relación Estructura-ActividadRESUMEN
Dopamine input to the dorsal and ventral striatum originates from separate populations of midbrain neurons. Despite differences in afferent inputs and behavioral output, little is known about how dopamine release is encoded by dopamine receptors on medium spiny neurons (MSNs) across striatal subregions. Here we examined the activation of D2 receptors following the synaptic release of dopamine in the dorsal striatum (DStr) and nucleus accumbens (NAc) shell. We found that D2 receptor-mediated synaptic currents were slower in the NAc and this difference occurred at the level of D2-receptor signaling. As a result of preferential coupling to Gαo, we also found that D2 receptors in MSNs demonstrated higher sensitivity for dopamine in the NAc. The higher sensitivity in the NAc was eliminated following cocaine exposure. These results identify differences in the sensitivity and timing of D2-receptor signaling across the striatum that influence how nigrostriatal and mesolimbic signals are encoded across these circuits.