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S.J.P.

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Discovery of conolidine derivative DS39201083 as a potent novel analgesic without mu opioid agonist activity
Corresponding author: Tsuyoshi Arita (R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan)
Bioorganic & Medicinal Chemistry Letters 2019, Volume 29, Issue 15, Pages 1938-1942
Published online May 21st, 2019
https://doi.org/10.1016/j.bmcl.2019.05.045
We discovered a novel compound, 5-methyl-1,4,5,7-tetrahydro-2,5-ethanoazocino[4,3-b]indol-6(3H)-one sulfuric acid salt (DS39201083), which was formed by derivatization of a natural product, conolidine. DS39201083 had a unique bicyclic skeleton and was a more potent analgesic than conolidine, as revealed in the acetic acid-induced writhing test and formalin test in ddY mice. The compound showed no agonist activity at the mu opioid receptor.
 

sekio

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Science. 2015 Sep 4;349(6252):1095-100. doi: 10.1126/science.aac9373. Epub 2015 Aug 13.
Complete biosynthesis of opioids in yeast.
Galanie S, Thodey K, Trenchard IJ, Filsinger Interrante M, Smolke CD.


Opioids are the primary drugs used in Western medicine for pain management and palliative care. Farming of opium poppies remains the sole source of these essential medicines, despite diverse market demands and uncertainty in crop yields due to weather, climate change, and pests. We engineered yeast to produce the selected opioid compounds thebaine and hydrocodone starting from sugar. All work was conducted in a laboratory that is permitted and secured for work with controlled substances. We combined enzyme discovery, enzyme engineering, and pathway and strain optimization to realize full opiate biosynthesis in yeast. The resulting opioid biosynthesis strains required the expression of 21 (thebaine) and 23 (hydrocodone) enzyme activities from plants, mammals, bacteria, and yeast itself. This is a proof of principle, and major hurdles remain before optimization and scale-up could be achieved. Open discussions of options for governing this technology are also needed in order to responsibly realize alternative supplies for these medically relevant compounds.
 

polymath

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^ Those genes could be inserted in the gut microbes of someone who has a huge opioid tolerance, as an alternative to methadone maintenance... Well, maybe not... :)
 

polymath

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The alkaloid glaucine, found in some poppy plants, is a real 5-HT2A agonist...


Abstract
Compounds with activity at serotonin (5-hydroxytryptamine) 5-HT2 and α1 adrenergic receptors have potential for the treatment of central nervous system disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesized, and their in vitro functional activities at human 5-HT2 and adrenergic α1 receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5-HT2 and α1 receptors with (R)-isolaureline showing the greatest potency (pKb = 8.14 at the 5-HT2C receptor). Both (R)- and (S)-glaucine also antagonized α1 receptors, but they behaved very differently to the other compounds at 5-HT2 receptors: (S)-glaucine acted as a partial agonist at all three 5-HT2 receptor subtypes, whereas (R)-glaucine appeared to act as a positive allosteric modulator at the 5-HT2A receptor.
 

polymath

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^ There are some trip reports about it on Erowid and other places. Most people seem to say it makes you feel really tired, like an alpha-2-adrenergic agonist. I'd like to see a halogen or methyl substituent added to one of those aromatic rings, maybe it would increase the psychedelic component of the effect.

12619


Edit: BTW, I also added (anonymously) the reference above to the Wikipedia article about glaucine.
 
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S.J.P.

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Salvindolin elicits opioid system-mediated antinociceptive and antidepressant-like activities
Corresponding author: James O. Fajemiroye (Department of Pharmacology, Federal University of Goiás, Goiânia, Brazil)
Journal of Psychopharmacology 2019, Volume 33, Issue 7, Pages 865-881
Published online June 13th, 2019
https://doi.org/10.1177/0269881119849821
Background:

Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects.

Aims:

In this article, we present its new semisynthetic analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities.

Methods:

Competitive binding studies were performed for salvindolin with kappa opioid and mu opioid. The mouse model of nociception (acetic-acid-induced writhing, formalin, and hot plate tests), depression (forced swim and tail suspension tests), and the open field test, were used to evaluate antinociceptive, antidepressant-like, and locomotion effects, respectively, of salvindolin. We built a 3-D molecular model of the kappa opioid receptor, using a mu opioid X-ray crystal structure as a template, and docked salvindolin into the two proteins.

Results/outcomes:

Salvindolin showed affinity towards kappa opioid and mu opioid receptors but with 100-fold mu opioid preference. Tests of salvindolin in mice revealed good oral bioavailability, antinociceptive, and antidepressive-like effects, without locomotor incoordination. Docking of salvindolin showed strong interactions with the mu opioid receptor which matched well with experimental binding data. Salvindolin-induced behavioral changes in the hot plate and forced swim tests were attenuated by naloxone (nonselective opioid receptor antagonist) and/or naloxonazine (selective mu opioid receptor antagonist) but not by nor-binaltorphimine (selective kappa opioid receptor antagonist). In addition, WAY100635 (a selective serotonin 1A receptor antagonist) blocked the antidepressant-like effect of salvindolin.

Conclusions/interpretation:

By simple chemical modification, we were able to modulate the pharmacological profile of salvinorin A, a highly selective kappa opioid receptor agonist, to salvindolin, a ligand with preferential mu opioid receptor affinity and activity on the serotonin 1A receptor. With its significant antinociceptive and antidepressive-like activities, salvindolin has the potential to be an analgesic and/or antidepressant drug candidate.
 

polymath

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G. E. DiCarlo et al. "Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors", J Clin Invest. 2019. https://doi.org/10.1172/JCI127411.

Abstract

The precise regulation of synaptic dopamine (DA) content by the DA transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, autism spectrum disorder (ASD). An ASD-associated de novo mutation in the SLC6A3 gene resulting in a threonine-to-methionine substitution at site 356 (DAT T356M) was recently identified and has been shown to drive persistent reverse transport of DA (i.e., anomalous DA efflux) in transfected cells and to drive hyperlocomotion in Drosophila melanogaster. A corresponding mutation in the leucine transporter, a DAT-homologous transporter, promotes an outward-facing transporter conformation upon substrate binding, a conformation possibly underlying anomalous DA efflux. Here, we investigated in vivo the impact of this ASD-associated mutation on DA signaling and ASD-associated behaviors. We found that mice homozygous for this mutation displayed impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.
 

S.J.P.

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Novel Dimethyltyrosine–Tetrahydroisoquinoline Peptidomimetics with Aromatic Tetrahydroisoquinoline Substitutions Show in Vitro Kappa and Mu Opioid Receptor Agonism
Corresponding author: Henry I. Mosberg (Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, United States)
ACS Chemical Neuroscience 2019, Volume 10, Issue 8, Pages 3682-3689
Published online June 14th, 2019
https://doi.org/10.1021/acschemneuro.9b00250
The dimethyltyrosine–tetrahydroisoquinoline (Dmt-Tiq) scaffold was originally developed in the production of selective delta opioid receptor (DOR) antagonists. Installation of a 7-benzyl pendant on the tetrahydroisoquinoline core of this classic opioid scaffold introduced kappa opioid receptor (KOR) agonism. Further modification of this pendant resulted in retention of KOR agonism and the addition of mu opioid receptor (MOR) partial agonism, a bifunctional profile with potential to be used in the treatment of cocaine addiction.
The following compound was the most potent mu agonist in the paper:

14183
 
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