Psychotridine

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.

We report the first enantioselective total synthesis and stereochemical assignment of (-)-psychotridine. The application of our diazene-directed assembly of enantiomerically enriched cyclotryptamines afforded a highly convergent synthesis of the pentameric alkaloid, allowing its detailed structural assignment. Highlights of the synthesis include the introduction of four quaternary stereocenters with complete stereochemical control in a single step via the photoextrusion of three molecules of dinitrogen from an advanced intermediate and metal-catalyzed C-H amination reactions in challenging settings.

The chemical study of two Rubiaceae from New Caledonia, Psychotria lyciiflora and Psychotria oleoides, led to the isolation of several pyrrolidinoindoline alkaloids. Two dimers, the known meso-chimonanthine (9) and the new Nb-desmethyl-meso-chimonanthine (5), and a known trimer, hodgkinsine (1), have been isolated from P. lyciiflora. Hodgkinsine (1), quadrigemine C (2), isopsychotridine B (3), psychotridine (4), and three new alkaloids, quadrigemine I (6), oleoidine (7), and caledonine (8), have been isolated from P. oleoides. Structural assignments of the compounds were based on mass spectra analysis and 2D NMR experiments. A tentative stereochemical determination is made from 2D NMR experiments, circular dichroism study and chemical correlations. Some of these compounds are functional antagonists of somatostatine (SRIH).