• N&PD Moderators: Skorpio | thegreenhand

⫸STICKY⫷ The N&PD Recent Journal ARTICLE Club

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.
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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.
 
^ 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... :)
 
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.
 
^ 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.

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

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J Ethnopharmacol. 2019 Nov 15;244:112151. doi: 10.1016/j.jep.2019.112151. Epub 2019 Aug 9.
Sagas of the Solanaceae: Speculative ethnobotanical perspectives on the Norse berserkers.
Fatur K
ETHNOPHARMACOLOGICAL RELEVANCE:

The Norse berserkers were wild warriors of Scandinavia known to enter a trance-like state that allowed them to fight with increased strength and a rage that granted them immunity to many forms of harm in battle. Though many theories have been advanced as to the cause of this state, the most widely believed is that the intoxicating mushroom Amanita muscaria was used.

AIM OF THE STUDY:

The following article underlines the issues with this theory and provides an alternate intoxicant that fits with the reports of berserker behaviour much better: Hyoscyamus niger.

MATERIALS AND METHODS:

Literature from a variety of disciplines pertaining to history, toxicology, pharmacology, and botany was compiled to frame and support the argument.

RESULTS:

H. niger proved to be a more likely intoxicant used to induce the berserker rage state.

CONCLUSIONS:

With its anticholinergic tropane alkaloids and symptom profile, H. niger is a much more likely cause of the berserker state than A muscaria. Though there is not enough archaeological and historical evidence to prove or disprove this theory, it provides a novel explanation that is at present the most viable means of understanding the berserkers' trance.

My love for you is like a truck, Berserker
Would you like some making fuck, Berserker
 
Discovery of dual-acting opioid ligand and TRPV1 antagonists as novel therapeutic agents for pain
Corresponding author: Jeewoo Lee (Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, South Korea)
European Journal of Medicinal Chemistry 2019, Volume 182, Page 111634
Published online August 21st, 2019
https://doi.org/10.1016/j.ejmech.2019.111634
In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo, 49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic.
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The Neuroscience of Drug Reward and Addiction
Corresponding author:
Nora D. Volkow, Michael Michaelides, and Ruben Baler
National Institute on Drug Abuse, Bethesda, Maryland
Physiological Reviews 2019 99:4, 2115-2140
Published in print 1 October 2019

Drug consumption is driven by a drug’s pharmacological effects, which are experienced as rewarding, and is influenced by genetic, developmental, and psychosocial factors that mediate drug accessibility, norms, and social support systems or lack thereof. The reinforcing effects of drugs mostly depend on dopamine signaling in the nucleus accumbens, and chronic drug exposure triggers glutamatergic-mediated neuroadaptations in dopamine striato-thalamo-cortical (predominantly in prefrontal cortical regions including orbitofrontal cortex and anterior cingulate cortex) and limbic pathways (amygdala and hippocampus) that, in vulnerable individuals, can result in addiction. In parallel, changes in the extended amygdala result in negative emotional states that perpetuate drug taking as an attempt to temporarily alleviate them. Counterintuitively, in the addicted person, the actual drug consumption is associated with an attenuated dopamine increase in brain reward regions, which might contribute to drug-taking behavior to compensate for the difference between the magnitude of the expected reward triggered by the conditioning to drug cues and the actual experience of it. Combined, these effects result in an enhanced motivation to “seek the drug” (energized by dopamine increases triggered by drug cues) and an impaired prefrontal top-down self-regulation that favors compulsive drug-taking against the backdrop of negative emotionality and an enhanced interoceptive awareness of “drug hunger.” Treatment interventions intended to reverse these neuroadaptations show promise as therapeutic approaches for addiction.


Full text available from researchgate author profile

Decent general review.
 
A new four amino acid peptide mu agonist...

https://www.pnas.org/content/116/44/22353

Zoltan Dekan, Setareh Sianati, Arsalan Yousuf, Katy J. Sutcliffe, Alexander Gillis, Christophe Mallet, Paramjit Singh, Aihua H. Jin, Anna M. Wang, Sarasa A. Mohammadi, Michael Stewart, Ranjala Ratnayake, Frank Fontaine, Ernest Lacey, Andrew M. Piggott, Yan P. Du, Meritxell Canals, Richard B. Sessions, Eamonn Kelly, Robert J. Capon, Paul F. Alewood, MacDonald J. Christie, A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor, Proceedings of the National Academy of Sciences Oct 2019, 116 (44) 22353-22358; DOI: 10.1073/pnas.1908662116

An Australian estuarine isolate of Penicillium sp. MST-MF667 yielded 3 tetrapeptides named the bilaids with an unusual alternating LDLD chirality. Given their resemblance to known short peptide opioid agonists, we elucidated that they were weak (Ki low micromolar) μ-opioid agonists, which led to the design of bilorphin, a potent and selective μ-opioid receptor (MOPr) agonist (Ki 1.1 nM). In sharp contrast to all-natural product opioid peptides that efficaciously recruit β-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting β-arrestin, with no receptor internalization. Importantly, bilorphin exhibits a similar G protein bias to oliceridine, a small nonpeptide with improved overdose safety. Molecular dynamics simulations of bilorphin and the strongly arrestin-biased endomorphin-2 with the MOPr indicate distinct receptor interactions and receptor conformations that could underlie their large differences in bias. Whereas bilorphin is systemically inactive, a glycosylated analog, bilactorphin, is orally active with similar in vivo potency to morphine. Bilorphin is both a unique molecular tool that enhances understanding of MOPr biased signaling and a promising lead in the development of next generation analgesics.
 
Discovery of Novel Biased Opioid Receptor Ligands through Structure‐Based Pharmacophore Virtual Screening and Experiment
Corresponding authors: Yong-Chul Kim (Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Buk-gu, South Korea) and William A. Goddard, III (Materials and Process Simulation Center, California Institute of Technology, Pasadena, United States)
ChemMedChem 2019, Volume 14, Issue 20, Pages 1783-1794
Published online September 26th, 2019
https://doi.org/10.1002/cmdc.201900418
Gi‐protein‐biased agonists with minimal β‐arrestin recruitment represent opportunities to overcome the serious adverse effects of human mu opioid receptor (μ‐OR) agonists and developing alternative and safe treatments for pain. In order to discover novel non‐morphinan opioid receptor agonists, we applied hierarchical virtual screening of our in‐house database against a pharmacophore based on modeling the active conformations of opioid receptors. We discovered an initial hit compound, a novel μ‐OR agonist with a pyrazoloisoquinoline scaffold. We applied computational R‐group screening to this compound and synthesized 14 derivatives predicted to be the best. Of these, a new Gi‐protein‐biased compound, 1‐{5‐(3‐chlorophenyl)‐7,8‐dimethoxy‐3‐[4‐(methylsulfonyl)benzyl]‐3H‐pyrazolo[3,4‐c]isoquinolin‐1‐yl}‐N,N‐dimethylmethanamine, showed an EC50 value of 179 nm against the μ‐OR. This resulted in significant pain relief for mice in the phase II period of formalin response tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for the development of drugs that target other G‐protein‐coupled receptors.
The most potent compound in the series at the mu opioid receptor:
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DARK Classics in Chemical Neuroscience: NBOMes
Authors: Christian B. M. Poulie, Anders A. Jensen, Adam L. Halberstadt, Jesper L. Kristensen*
ACS Chem. Neurosci. 2019,
Publication Date:October 28, 2019
https://doi.org/10.1021/acschemneuro.9b00528

N-Benzylphenethylamines, commonly known as NBOMes, are synthetic psychedelic compounds derived from the phenethylamine class of psychedelics (2C-X compounds), which originally have been derived from the naturally occurring alkaloid mescaline. Analogously to their parent compounds and other classical psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), NBOMes are believed to exert their main pharmacological effects through activation of serotonin 2A (5-HT2A) receptors. Since their introduction as New Psychoactive Substances (NPSs) in 2010, NBOMes have been widely used for recreational purposes; this has resulted in numerous cases of acute toxicity, sometimes with lethal outcomes, leading to the classification of several NBOMes as Schedule I substances in 2013. However, in addition to their recreational use, the NBOMe class has yielded several important biochemical tools, including [11C]Cimbi-36, which is now being used in positron emission tomography (PET) studies of the 5-HT2A and 5-HT2C receptors in the mammalian brain, and 25CN-NBOH, one of the most selective 5-HT2A receptor agonists developed to date. In this Review, the history, chemistry, structure–activity relationships, ADME (absorption, distribution, metabolism, and excretion) properties, and safety profiles of NBOMes will be outlined and discussed.

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Examining the short-term anxiolytic and antidepressant effect of Floatation-REST
Authors: Justin S. Feinstein, Sahib S. Khalsa, Hung-wen Yeh, Colleen Wohlrab, Murray B. Stein, Martin P. Paulus
PLoS One. 2018; 13(2): e0190292.
doi: 10.1371/journal.pone.0190292

Abstract
Floatation-REST (Reduced Environmental Stimulation Therapy) reduces sensory input to the nervous system through the act of floating supine in a pool of water saturated with Epsom salt. The float experience is calibrated so that sensory signals from visual, auditory, olfactory, gustatory, thermal, tactile, vestibular, gravitational and proprioceptive channels are minimized, as is most movement and speech. This open-label study aimed to examine whether Floatation-REST would attenuate symptoms of anxiety, stress, and depression in a clinical sample. Fifty participants were recruited across a spectrum of anxiety and stress-related disorders (posttraumatic stress, generalized anxiety, panic, agoraphobia, and social anxiety), most (n = 46) with comorbid unipolar depression. Measures of self-reported affect were collected immediately before and after a 1-hour float session, with the primary outcome measure being the pre- to post-float change score on the Spielberger State Anxiety Inventory. Irrespective of diagnosis, Floatation-REST substantially reduced state anxiety (estimated Cohen’s d > 2). Moreover, participants reported significant reductions in stress, muscle tension, pain, depression and negative affect, accompanied by a significant improvement in mood characterized by increases in serenity, relaxation, happiness and overall well-being (p < .0001 for all variables). In reference to a group of 30 non-anxious participants, the effects were found to be more robust in the anxious sample and approaching non-anxious levels during the post-float period. Further analysis revealed that the most severely anxious participants reported the largest effects. Overall, the procedure was well-tolerated, with no major safety concerns stemming from this single session. The findings from this initial study need to be replicated in larger controlled trials, but suggest that Floatation-REST may be a promising technique for transiently reducing the suffering in those with anxiety and depression.
 
Mystery of why magic mushrooms go blue solved
By Katrina Krämer
10 December 2019
Why do magic mushrooms turn blue when they are cut? Chemists have now unravelled this decade-old mystery, in the process revealing that the dark blue pigments at the centre of the mystery are similar to indigo, the dye used to produce blue jeans.
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Journal article: Injury‐Triggered Blueing Reactions of Psilocybe “Magic” Mushrooms
Claudius Lenz, Dr. Jonas Wick, Dr. Daniel Braga, Dr. María García‐Altares,Dr. Gerald Lackner, Prof. Dr. Christian Hertweck, Dr. Markus Gressler, Prof. Dr. Dirk Hoffmeister
Upon injury, psychotropic psilocybin‐producing mushrooms instantly develop an intense blue color, the chemical basis and mode of formation of which has remained elusive. We report two enzymes from Psilocybe cubensis that carry out a two‐step cascade to prepare psilocybin for oxidative oligomerization that leads to blue products. The phosphatase PsiP removes the 4‐O‐phosphate group to yield psilocin, while PsiL oxidizes its 4‐hydroxy group. The PsiL reaction was monitored by in situ 13C NMR spectroscopy, which indicated that oxidative coupling of psilocyl residues occurs primarily via C‐5. MS and IR spectroscopy indicated the formation of a heterogeneous mixture of preferentially psilocyl 3‐ to 13‐mers and suggest multiple oligomerization routes, depending on oxidative power and substrate concentration. The results also imply that phosphate ester of psilocybin serves a reversible protective function.
https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201910175
 
Biological psychiatry has a whole free issue on the "Neurobiology of the Opioid Epidemic"



Example article:

Molecular Basis of Opioid Action: From Structures to New Leads
Author: Manglik, Aashish
2020. Biological Psychiatry, Volume 87, Issue 1, 6 - 14.


Since the isolation of morphine from the opium poppy over 200 years ago, the molecular basis of opioid action has remained the subject of intense inquiry. The identification of specific receptors responsible for opioid function and the discovery of many chemically diverse molecules with unique opioid-like efficacies have provided glimpses into the molecular logic of opioid action. Recent revolutions in the structural biology of transmembrane proteins have, for the first time, yielded high-resolution views into the 3-dimensional shapes of all 4 opioid receptors. These studies have begun to decode the chemical logic that enables opioids to specifically bind and activate their receptor targets. A combination of spectroscopic experiments and computational simulations has provided a view into the molecular movements of the opioid receptors, which itself gives rise to the complex opioid pharmacology observed at the cellular and behavioral levels. Further diversity in opioid receptor structure is driven by both genetic variation and receptor oligomerization. These insights have enabled computational drug discovery efforts, with some evidence of success in the design of completely novel opioids with unique efficacies. The combined progress over the past few years provides hope for new, efficacious opioids devoid of the side effects that have made them the scourge of humanity for millennia.

Doi: https://doi.org/10.1016/j.biopsych.2019.08.028
 
Polo Sara, Díaz Andrés Felipe, Gallardo Núria, Leánez Sergi, Balboni Gianfranco, Pol Olga, "Treatment With the Delta Opioid Agonist UFP-512 Alleviates Chronic Inflammatory and Neuropathic Pain: Mechanisms Implicated", Frontiers in Pharmacology, Volume 10, 2019, page 283.


We investigated whether administration of the δ-opioid receptor (DOR) agonist H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512), which also activates nuclear factor erythroid 2-related factor 2 (Nrf2), alleviated chronic inflammatory and/or neuropathic pain and inhibited the depressive-like behaviors associated with persistent neuropathic pain. The possible mechanisms implicated were also assessed. We evaluated the following effects in male C57BL/6J mice with inflammatory pain induced by complete Freund’s adjuvant or neuropathic pain caused by the chronic constriction of sciatic nerve: (1) the antinociceptive effects of UFP-512; (2) the effects of UFP-512 on the expression of Nrf2, heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1, phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), inducible nitric oxide synthase, DOR, and mitogen-activated protein kinases (MAPK) in the spinal cord of animals with inflammatory or neuropathic pain; (3) the antinociceptive effects of the coadministration of UFP-512 with the Nrf2 activator sulforaphane (SFN); and (4) the antidepressant effects of UFP-512 in animals with depressive-like behaviors associated with neuropathic pain. Our results demonstrated that the intraperitoneal administration of UFP-512 inhibited chronic inflammatory and neuropathic pain and reduced the depressive-like behaviors associated with persistent neuropathic pain. The antiallodynic effects of UFP-512 were significantly augmented when it was coadministered with SFN in both types of chronic pain. The administration of UFP-512 increased/reestablished the spinal cord protein levels of Nrf2 and HO-1 in mice with inflammatory or neuropathic pain. However, while during inflammatory pain UFP-512 inhibited spinal c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation induced by peripheral inflammation. This DOR agonist blocked the spinal activated PI3K/Akt signaling pathway under chronic neuropathic pain conditions, but it did not alter the enhanced protein levels of p-JNK or p-ERK1/2 induced by sciatic nerve injury. These results revealed the antinociceptive and antidepressant effects of UFP-512 in animals with chronic pain and the different mechanism of action of this DOR agonist in the presence of inflammatory or neuropathic pain. Our data also suggest the administration of UFP-512 as an alternative for the treatment of chronic pain and the depressive-like behaviors associated with neuropathic pain.

Selective delta agonists are said to have a cocaine-like stimulant effect in some experiments, but OTOH also morphine is a locomotor stimulant for cats so it's difficult to say how a selective delta ligand would affect a human.
 
A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-Tetrahydrocannabiphorol Cinzia Citti, Pasquale Linciano, Fabiana Russo, Livio Luongo, Monica Iannotta, Sabatino Maione, Aldo Laganà, Anna Laura Capriotti, Flavio Forni, Maria Angela Vandelli, Giuseppe Gigli & Giuseppe Cannazza
Scientific Reports volume 9, Article number: 20335 (2019)
(-)-Trans-Δ9-tetrahydrocannabinol (Δ9-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Δ9-THC with a longer side chain have shown cannabimimetic properties far higher than Δ9-THC itself. In the attempt to define the phytocannabinoids profile that characterizes a medicinal cannabis variety, a new phytocannabinoid with the same structure of Δ9-THC but with a seven-term alkyl side chain was identified. The natural compound was isolated and fully characterized and its stereochemical configuration was assigned by match with the same compound obtained by a stereoselective synthesis. This new phytocannabinoid has been called (-)-trans-Δ9-tetrahydrocannabiphorol (Δ9-THCP). Along with Δ9-THCP, the corresponding cannabidiol (CBD) homolog with seven-term side alkyl chain (CBDP) was also isolated and unambiguously identified by match with its synthetic counterpart. The binding activity of Δ9-THCP against human CB1 receptor in vitro (Ki = 1.2 nM) resulted similar to that of CP55940 (Ki = 0.9 nM), a potent full CB1 agonist. In the cannabinoid tetrad pharmacological test, Δ9-THCP induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating a THC-like cannabimimetic activity. The presence of this new phytocannabinoid could account for the pharmacological properties of some cannabis varieties difficult to explain by the presence of the sole Δ9-THC.
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So this is basically the opposite direction from THCV... neat.
 
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