5-HT2A Receptor Knockout Mice Show Sex-Dependent Differences following Acute Noribogaine Administration.

Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga. The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT2A receptor (5-HT2AR) in mice. In that regard, we used male and female, 5-HT2AR knockout (KO) and wild type (WT) mice injected with a single noribo dose (10 or 40 mg/kg; i.p.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT2AR levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT2AR mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT2AR blunted noribo-mediated responses to NMDA synaptic transmission.

Efficient Access to the Iboga Skeleton: Optimized Procedure to Obtain Voacangine from Voacanga africana Root Bark.

Iboga alkaloids are a group of monoterpenoid indole alkaloids with promising and intriguing biological activities. Ibogaine is the representative member of the series and has become widely known as a potent atypical psychedelic with promising effects to treat substance use disorder. Nowadays, an efficient and scalable enantioselective total synthesis of ibogaine and related iboga alkaloids is still lacking, so direct extraction from natural sources or semi-synthetic schemes are the methods of choice to obtain them in a preparative scale. In particular, ibogaine can be obtained either by a low yielding direct isolation from Tabernanthe iboga or using a semi-synthetic procedure from voacangine, an iboga alkaloid occurring in a higher yield in the root bark of Voacanga africana. In this work, we describe an optimized process to obtain voacangine from V. africana root bark as a precursor of the iboga scaffold. Using a direct acetone-based extraction procedure (0.5 kg of root bark), voacangine was isolated in ∼0.8% of root bark dried weight, while the major alkaloids isolated from the bark were identified as iboga-vobasinyl dimers (∼3.7%) such as voacamine and voacamidine. Since these alkaloids contain the voacangine moiety in their structure, the cleavage of the dimers was further optimized, affording an extra amount of voacangine in ∼50% isolated molar yield. In this manner, the total amount of voacangine obtained by application of the whole procedure to the plant material (extraction and dimer cleavage) could almost duplicate the content originally found in the root bark.

Synthesis, Profiling, and in Vivo Evaluation of Cyclopeptides Containing N-Methyl Amino Acids as Antiplasmodial Agents.

Malaria is a major tropical disease where important needs are to mitigate symptoms and to prevent the establishment of infection. Cyclopeptides containing N-methyl amino acids with in vitro activity against erythrocytic forms as well as liver stage are presented. The synthesis, parasitological characterization, physicochemical properties, in vivo evaluation, and mice pharmacokinetics are described.

Synthesis of Cyclic Peptides as Potential Anti-Malarials.

The results from the synthesis of peptides by Fmoc/SPPS on a 2-CTC resin and then lactamization in solution or solid phase for the preparation of cyclopeptides are presented. Both procedures allow the synthesis of the desired compounds in good to very good yield and with high cyclization efficiency for on-resin macrocyclization. In addition, the activities of the corresponding cyclopeptides against the chloroquine-resistant K1 strain of Plasmodium falciparum were evaluated. Cyclo-Cys(Trt)-Gly-Thr( tBu)-Gly-Cys(Trt)-Gly showed potent in vitro and selective activity against this parasite, EC50 = 28 nM.

Chemoselective and Sequential Palladium-Catalyzed Couplings for the Generation of Stilbene Libraries via Immobilized Substrates.

A versatile palladium-catalyzed tandem synthetic sequence to afford E-stilbenes libraries has been developed. Excellent regio- and stereocontrol have been achieved by means of the sequence of Hiyama and Heck cross-couplings. Undesirable homocoupling byproducts were avoided employing immobilized substrates.