Abstract
The first stage of the drug discovery process involves the identification of small compounds with biological activity. Iboga alkaloids are monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring. Both the natural products and the iboga-inspired synthetic analogs have shown a wide variety of biological activities. Herein, we describe the chemoenzymatic preparation of a small library of novel N-indolylethyl-substituted isoquinuclidines as iboga-inspired compounds, using toluene as a starting material and an imine Diels–Alder reaction as the key step in the synthesis. The new iboga series was investigated for its potential to promote the release of glial cell line-derived neurotrophic factor (GDNF) by C6 glioma cells, and to inhibit the growth of infective trypanosomes. GDNF is a neurotrophic factor widely recognized by its crucial role in development, survival, maintenance, and protection of dopaminergic neuronal circuitries affected in several neurological and psychiatric pathologies. Four compounds of the series showed promising activity as GDNF releasers, and a leading structure (compound 11) was identified for further studies. The same four compounds impaired the growth of bloodstream Trypanosoma brucei brucei (EC50 1–8 μM) and two of them (compounds 6 and 14) showed a good selectivity index.
Highlights
Indole alkaloids have been a large source of bioactive compounds for drug discovery
Iboga alkaloids are a group of monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring, that have been investigated for their wide variety of fascinating pharmacological effects
We recently reported that ibogaine induces a dose-dependent upregulation of glial cell-derived neurotrophic factor (GDNF) in specific rat brain regions related to the mesocorticolimbic and nigral dopaminergic circuits [2], an effect which was previously proposed as a molecular mechanism underlying the attenuation of drug self-administration and drug craving by ibogaine [3]
Summary
Iboga alkaloids are a group of monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring, that have been investigated for their wide variety of fascinating pharmacological effects. The main representative of the group, is a potent atypical psychedelic agent with promising potential to treat substance use disorders (SUD), as evidenced by preclinical self-administration animal models and open-label studies in humans (Figure 1) [1]. We recently reported that ibogaine induces a dose-dependent upregulation of glial cell-derived neurotrophic factor (GDNF) in specific rat brain regions related to the mesocorticolimbic and nigral dopaminergic circuits [2], an effect which was previously proposed as a molecular mechanism underlying the attenuation of drug self-administration and drug craving by ibogaine [3]. Alteration in GDNF expression has been related to several neurological pathologies, such as SUD, Parkinson’s
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