I'm surprised that more people are not as enthusiastic as myself regarding the potential of these marine derived indole and tryptamine compounds....
https://www.ncbi.nlm.nih...C2922063/?report=classicAccording to the World Health Organization, major depression will become the second leading cause of death by the year 2020 due to the complications arising from cardiovascular system and stress.61 There is a tremendous unmet need for new, safer and more effective antidepressant drugs since currently used antidepressants have significant side effects and about 30% of the population does not respond to these current treatments.62 Marine natural products have been overlooked as potent neurologically active molecules, considered primarily as anticancer and antimicrobial leads.
Marine indole alkaloids represent a rich group of natural compounds and have tremendous potential to become new drug leads for various psychiatric disorders as well as to provide better insights into the understanding of serotonin receptor function. These molecules are reasonable synthetic targets which further enhances their value as possible drug leads, however few if any have been prepared as part of synthetic or medicinal chemistry studies designed to generate optimized leads for depression and anxiety.
Misc. Fun from the article:
https://www.ncbi.nlm.nih...C2922063/?report=classicResearch completed by Blair and co-workers43 on thieno[3,2-b]- and thieno[2,3-b] pyrrole bioisosters of N,N-dimethyltryptamine revealed that thiophene cannot serve as a replacement for the phenyl ring in the indole moiety of tryptamines which bind to 5HT2 receptors. However, thiophene can be a suitable bioisostere for compounds possessing activity to 5HT1A receptor. Another paper by Blair et al. reports the effect of ring fluorination on the activity of hallucinogenic tryptamines.44 According to their findings, fluorination of tryptamines in positions 4, 5, 6, and 7 reduces hallucinogenic activity. Introducing fluorine at the 6 position of 5-methoxy-N,N-dimethyltryptamine decreases the 5HT1A receptor binding affinity. For example, compound 73 exhibited a Ki of 84.5 nM, while compound 70 exhibited a Ki of 1.7 nM. In the case of N,N-dimethyltryptamine, fluorination at position 6 caused a 5 fold decrease in affinity towards the 5HT1A receptor (compound 69 versus 75).
Fluorination of 5-methoxy-N,N-dimethyltryptamine at position 4 led to increased affinity towards the 5-HT1A receptor and resulted in potent and selective 4-fluoro-5-methoxy-N,N-dimethyltryptamine (74) with a Ki of 0.23 nM (compared to a Ki of 1.7 nM for compound 70). In the case of 5HT2A and 5HT2C receptors, fluorination at position 6 has only insignificant effects on the affinity to these receptors. Chen et al. described the process of preparation of N-(2-arylethyl)benzamines (compounds 76-82) as antagonists of 5HT6 receptors.45 Authors disclosed the use of these antagonists to treat cognitive dysfunction and any disorders associated with 5HT6 receptors: age-related cognitive disorders, anxiety, schizophrenia, Parkinson's disease, epilepsy, convulsions, migraine, and sleep disorders.
In 1998, Audia et al. presented several 8-substituted tetrahydro-beta-carboline compounds and tryptamine-like intermediates possessing high affinity towards all the subtypes of 5HT2 receptors.46 Compounds 83-89 were prepared to serve as molecular tools to develop selective therapeutic 5HT2A and 5HT2C agents, as well as to become effective drugs by themselves. Another patent publication by Audia et al. describes compounds 90-104 with affinity towards 5HT2A, 5HT2B and 5HT2C which could be useful in the treatment of various disorders associated with these receptors, including tachygastria, ichlasia, dyspepsia, schizophrenia, anxiety, depression and migraines.47 Indole derivatives 105, 106 and 107 and their affinity to 5HT2 receptors were the subject of a patent published in 1995 by Audia et al.48 This publication claimed the use of the aforementioned compounds to protect or to treat mammals suffering from 5HT2 receptor related disorders such as hypertension, depression and anxiety. Compounds 108, 109, 110, 112 and 113 were disclosed as inhibitors of angiogenesis, which plays a crucial role in the pathogenesis of cancer, immune and inflammatory disorders.49
Another subtype of serotonin receptors, 5-HT7, has been recently linked to psychiatric disorders like depression and schizophrenia, but their function still remains largely unknown. Vermeulen et al. presented a comprehensive study of inverse agonists of these receptors and determined that tryptamine derivatives like compound 111 without additional aromatic rings exhibit only poor affinity towards these receptors.50
A series of enantiomeric pairs of α-methyltryptamines was investigated by Nichols et al.51 The authors tested tryptamine analogues in 5HT1B and 5HT2 receptor binding assays and showed that enantioselectivity at both binding sites varied depending on the aromatic substituents. At both receptor subtypes, the order of affinity for the α-methyltryptamines was 5-substituted (116) > 4-substituted (115) > unsubstituted (114) > 6-substituted (117). In the case of 5-hydroxy-α-methyltryptamine (119) an S isomer had higher affinity to both receptors over the R isomer. For compounds 115 and 118, the R isomers exhibited higher affinity at the 5HT1B receptor but not at the 5HT2.
-eg
entheogenic-gnosis attached the following image(s):
nihms195524f10.jpg
(51kb) downloaded 102 time(s). nihms195524f3a.jpg
(25kb) downloaded 99 time(s). nihms195524f2.jpg
(36kb) downloaded 97 time(s).