RESUMO
Hodgkinsine, a trimeric pyrrolidinoindoline type alkaloid, present as a major constituent of Psychotria spp. (Rubiaceae), has shown to produce dose-dependent, naloxone reversible, analgesic effect in thermal models of nociception and in the capsaicin-induced pain. SAR studies have been initiated by synthesizing the three diastereomeric dimers (chimonanthines) (11-13) which were evaluated in vitro and in vivo along with the synthetic intermediates. Strong binding affinities for mu opioid receptors were found for (-)- and (+)-chimonanthine monourethanes (9 and 10), whereas (-)-, (+)- and (meso)-chimonanthine (11-13) and hodgkinsine displayed low affinity. In vivo data have shown that only (+)-chimonanthine (12) and calycosidine resemble the analgesic profile found for hodgkinsine.
Assuntos
Alcaloides/síntese química , Alcaloides/farmacologia , Analgésicos/síntese química , Analgésicos/farmacologia , Pirróis/química , Alcaloides/química , Analgésicos/químicaRESUMO
We have previously reported that the alkaloid extract of Psychotria colorata (Willd. ex R. & S.) Muell. Arg., had marked dose-dependent, opioid-like activity. Phytochemical analyses of P. colorata flowers and leaves identified several pyrrolidinoindoline alkaloids, including psychotridine. To further investigate the activity and mechanism of action of Psychotria alkaloids, we studied the effects of psychotridine on thermal and chemical models of analgesia. In the tail-flick model, psychotridine presents a dose-dependent analgesic effect; the effect is not reversed by prior treatment with naloxone. Psychotridine dose-dependently decreased capsaicin-induced pain. Performance in the rotarod test showed that psychotridine does not induce motor deficits at doses effective in analgesia models. Psychotridine inhibited [3H]MK-801 (dizocilpine) binding to cortex membranes in a dose-dependent manner. Binding is completely abolished at 300 nM. The data rule out opioid activity, and the inhibition of capsaicin-induced pain and of radioligand binding strongly suggest the participation of NMDA receptors in psychotridine-induced analgesia.
Assuntos
Alcaloides/farmacologia , Analgésicos/farmacologia , Indóis/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Rubiaceae/química , Analgésicos/química , Analgésicos Opioides/farmacologia , Animais , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Indóis/química , Masculino , Camundongos , Estrutura Molecular , Morfina/farmacologia , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Estruturas VegetaisRESUMO
To further understand the mechanism of analgesic activity and structural requirements of pyrrolidinoindoline alkaloids identified in Psychotria colorata, we here report the analgesic activity of the trimer hodgkinsine on thermal and chemical models of analgesia. Results show that hodgkinsine produces a dose-dependent naloxone reversible analgesic effect in thermal models of nociception, suggesting that activation of opioid receptors participates in hodgkinsine's mode of action. Hodgkinsine shows a potent dose-dependent analgesic activity against capsaicin-induced pain, indicating the participation of NMDA receptors in hodgkinsine-induced analgesia. Such a dual mechanism of action may be of interest for developing innovative analgesics.
Assuntos
Analgésicos não Narcóticos/farmacologia , Indóis/farmacologia , Rubiaceae/química , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/isolamento & purificação , Animais , Indóis/química , Indóis/isolamento & purificação , Masculino , Camundongos , Estrutura MolecularRESUMO
An ethnopharmacological survey showed that home remedies prepared with flowers and fruits of Psychotria colorata are used by Amazonian peasants as pain killers. Psychopharmacological in vivo evaluation of alkaloids obtained from leaves and flowers of this species showed a marked dose-dependent naloxone-reversible analgesic activity, therefore suggesting an opioid-like pharmacological profile. This paper reports an inhibitory effect of P. colorata flower alkaloids on [3H]naloxone binding in rat striata as well as a decrease in adenylate cyclase basal activity. The alkaloids did not affect [3H] GMP-PNP binding. These findings provide a neurochemical basis for the opioid-like activity previously detected in vivo and point to Psychotria alkaloids as a potential source of new bioactive opiate derivatives.
Assuntos
Alcaloides/farmacologia , Analgésicos Opioides/farmacologia , Encéfalo/efeitos dos fármacos , Plantas Medicinais , Adenilil Ciclases/efeitos dos fármacos , Animais , Proteínas de Ligação ao GTP/metabolismo , Masculino , Membranas/efeitos dos fármacos , Membranas/metabolismo , Morfina/farmacologia , Naloxona/metabolismo , Ensaio Radioligante , Ratos , Ratos WistarRESUMO
An ethnopharmacological survey showed that home remedies prepared with flowers, fruits and roots of Psychotria colorata (Wild. ex R. & S.) Muell. Arg. (RUBIACEAE) are used by Amazonian caboclos as pain killers. These data led to the evaluation of analgesic activity of extracts of P. colorata, using the formalin, writhing and tail-flick methods. This paper reports the Naloxone reversible opioid-like analgesic activity of alkaloids present in leafs and flowers of P. colorata.