Endocannabinoid System: nootropics and compounds | sci-wiki

2-Arachidonoylglycerol

2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid (endocannabinoid) that serves as the principal full agonist of the CB1 and CB2 cannabinoid receptors in the mammalian body. A monoacylglycerol built from arachidonic acid esterified to glycerol, it was isolated from rat brain and canine gut in 1995 and is now regarded as the most abundant endocannabinoid in the central nervous system. Unlike a stored transmitter, 2-AG is synthesized on demand from membrane phospholipids by sn-1-diacylglycerol lipases (DAGL-alpha and DAGL-beta) in response to elevated intracellular calcium, then released to act as a retrograde messenger at synapses before being rapidly hydrolyzed back to arachidonic acid and glycerol by monoacylglycerol lipase (MAGL). Through this signaling it modulates synaptic plasticity, pain, appetite, mood, neuroinflammation, and immune and cardiovascular function, and it is a central node of the wider endocannabinoid system.

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Cannabinoid

AM3506

AM3506 is an investigational fatty acid amide hydrolase (FAAH) inhibitor of the sulfonyl fluoride chemical class that raises brain levels of the endocannabinoid anandamide by irreversibly blocking the enzyme that degrades it. Developed at Northeastern University's Center for Drug Discovery (Makriyannis group) and characterized largely in collaboration with the National Institutes of Health, it is a potent, selective, covalent inhibitor of both rat and human FAAH. In preclinical models it normalizes blood pressure in hypertensive rats, promotes fear extinction through the amygdala, and restores endotoxin-disturbed gastrointestinal motility, all via downstream CB1/CB2 receptor signaling. AM3506 has not entered human clinical trials and remains a research compound.

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Cannabinoid

BIA 10-2474

BIA 10-2474 is an investigational, orally active fatty acid amide hydrolase (FAAH) inhibitor developed by the Portuguese pharmaceutical company Bial as a candidate treatment for chronic pain, anxiety, and mood disorders. By blocking FAAH, the enzyme that degrades the endocannabinoid anandamide, it was intended to raise endocannabinoid tone and produce analgesic and anxiolytic effects. In January 2016 a Phase 1 healthy-volunteer trial in Rennes, France produced an unanticipated, rapidly progressive neurologic syndrome in the high repeated-dose cohort: one volunteer died and several others were hospitalized with symmetric brain lesions. Development was halted, and subsequent proteomic work showed the compound is a promiscuous inhibitor of multiple lipases and off-target enzymes rather than a selective FAAH blocker. It is now regarded as a landmark case study in drug-safety science and is not available or used outside that historical and investigational context.

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Cannabinoid

Cannabichromene

Cannabichromene (CBC) is a non-psychotropic phytocannabinoid and one of the six most abundant cannabinoids in Cannabis sativa, biosynthesized from cannabigerolic acid (CBGA) via the enzyme CBCA synthase and decarboxylated from its acidic precursor cannabichromenic acid. Structurally a resorcinol-derived chromene rather than the classic dibenzopyran of THC, it binds the classical cannabinoid receptors only weakly and instead acts primarily as a potent agonist of the TRPA1 ion channel while inhibiting the cellular reuptake and degradation of the endocannabinoid anandamide. Preclinical studies describe anti-inflammatory, gastrointestinal-normalizing, antidepressant-like, analgesic, antimicrobial and neural stem-cell-supporting activity, and CBC is frequently cited as a contributor to the "entourage effect" of whole-plant cannabis. It is not scheduled as a distinct controlled substance in most jurisdictions but is regulated as a cannabis constituent, and its clinical evidence base in humans remains early-stage.

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Cannabinoid

CP-55,940

CP-55,940 is a synthetic non-classical cannabinoid that acts as a potent, non-selective full agonist at the CB1 and CB2 cannabinoid receptors. Developed by Pfizer in the 1970s during a search for cannabinoid-based analgesics, it lacks the classic tricyclic dibenzopyran ring of THC yet reproduces the full cannabinoid pharmacological profile with far greater potency. Its tritiated form, [3H]CP-55,940, became the standard radioligand used to detect, clone, and map cannabinoid receptors, making the compound a foundational reference tool in endocannabinoid research rather than a therapeutic or consumer product.

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Cannabinoid

HU-210

HU-210 is a synthetic cannabinoid that acts as an ultra-potent full agonist at both the CB1 and CB2 cannabinoid receptors. It is the (6aR,10aR) enantiomer of the 1,1-dimethylheptyl homolog of 11-hydroxy-delta-8-tetrahydrocannabinol, developed in the 1980s by Raphael Mechoulam's group at the Hebrew University of Jerusalem (the source of the "HU" prefix). Structurally a close analog of THC, HU-210 is estimated to be roughly 100 to 800 times more potent than delta-9-THC, with sub-nanomolar affinity at CB1 and a notably long duration of action. It has been used primarily as a pharmacological tool compound to probe the endocannabinoid system in preclinical models, and has also appeared as an adulterant in illicit "herbal incense" (Spice/K2) products. HU-210 is controlled as a Schedule I substance in the United States and is not an approved medicine.

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Cannabinoid

HU-308

HU-308 is a synthetic cannabinoid that acts as a highly selective agonist of the type-2 cannabinoid receptor (CB2), the peripheral and immune-cell arm of the endocannabinoid system. First reported in 1999 by Raphael Mechoulam's group at the Hebrew University of Jerusalem, it was designed as a nonpsychotropic probe: it binds CB2 with nanomolar affinity (Ki ~22.7 nM) while showing essentially no affinity for the centrally expressed CB1 receptor (Ki > 10 microM), so it produces none of the tetrahydrocannabinol-type behavioral effects mediated by CB1. Through CB2 activation it lowers blood pressure, blocks defecation, and exerts anti-inflammatory and peripheral analgesic activity, effects reversed by the CB2 antagonist SR-144528 but not by the CB1 antagonist rimonabant. Across preclinical models it dampens pro-inflammatory cytokine release from macrophages and microglia, and it has been studied in acute lung injury, collagen-induced arthritis, endothelial activation, Parkinsonian neuroinflammation, and proliferative vitreoretinopathy. HU-308 remains an investigational research compound and is not an approved drug.

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Synthetic Cannabinoid

MDMB-4en-PINACA

MDMB-4en-PINACA is a synthetic cannabinoid, an indazole carboxamide sold sprayed onto plant material and into vape liquid. ⚠️ It is not strong cannabis. THC is a partial agonist at the CB1 receptor and therefore has a ceiling; this is a full agonist and has none, reaching roughly 2.4 times THC's maximum effect and about 27 times its potency in the same experiment [1]. In the largest clinical series, 81 percent of presentations involved reduced consciousness and 30 percent involved seizures [3].

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Cannabinoid

OL-135

OL-135 is a reversible, competitive fatty acid amide hydrolase (FAAH) inhibitor of the alpha-ketoheterocycle class, developed by the Boger laboratory at The Scripps Research Institute as a chemical tool to raise endogenous anandamide. Built around an electrophilic alpha-ketooxazole warhead (a pyridyl-activated ketone), it inhibits FAAH in the low-nanomolar range and is selective over other serine hydrolases. Unlike the irreversible carbamate inhibitor URB597, OL-135 binds the enzyme reversibly, forming a deprotonated hemiketal with the catalytic serine that mimics the tetrahedral reaction intermediate. In rodent studies it elevates brain anandamide and produces cannabinoid-receptor-mediated analgesia, anti-allodynia, anti-pruritic and anti-inflammatory effects without the overt psychoactivity of direct CB1 agonists. OL-135 remains an investigational research compound; it never advanced to human clinical trials, but it served as the lead scaffold for a large family of orally active, long-acting FAAH inhibitors.

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Cannabinoid

PF-04457845

PF-04457845 is an investigational, orally bioavailable fatty acid amide hydrolase (FAAH) inhibitor developed by Pfizer that raises endocannabinoid tone by blocking the enzyme responsible for degrading anandamide. It is a highly potent, exquisitely selective, covalent (irreversible) inhibitor that carbamylates FAAH's catalytic serine, inhibiting the human enzyme with an IC50 of roughly 7.2 nM. Because it amplifies the body's own cannabinoid signaling rather than directly activating CB1 receptors, it elevates anandamide (and related fatty acid amides) without the intoxication, cognitive impairment, or motor side effects associated with direct CB1 agonists such as THC. In clinical testing it achieved greater than 96% FAAH inhibition and a roughly ten-fold rise in circulating anandamide, and it has been studied for osteoarthritis pain, cannabis use disorder, and stress- and fear-related conditions such as post-traumatic stress disorder. It failed to beat placebo in an osteoarthritis knee-pain trial but showed positive signals for cannabis withdrawal and fear extinction, and it remains a widely used pharmacological tool for probing the endocannabinoid system.

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Cannabinoid

PF-3845

PF-3845 is a highly selective, covalent fatty acid amide hydrolase (FAAH) inhibitor developed by Pfizer as a pharmacological tool to augment endocannabinoid signaling in vivo. By carbamylating the serine nucleophile of FAAH, the enzyme responsible for degrading the endocannabinoid anandamide, PF-3845 raises brain and peripheral levels of anandamide and related N-acylethanolamines for up to 24 hours after a single dose. It is widely used in preclinical neuroscience to probe endocannabinoid contributions to pain, inflammation, anxiety, and nausea, and remains an investigational research compound rather than an approved drug.

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Cannabinoid

Rimonabant

The first CB1 cannabinoid-receptor blocker; a withdrawn anti-obesity drug (Acomplia) that curbed appetite and cleaned up metabolic markers, but was pulled worldwide for serious psychiatric risk.

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Cannabinoid

URB597

URB597, also known as KDS-4103, is a potent and selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme that breaks down the endocannabinoid anandamide. By blocking FAAH, URB597 raises anandamide levels and amplifies endocannabinoid signaling, producing anxiolytic, antidepressant-like, and analgesic effects in animal models without the full intoxicating profile of direct cannabinoid agonists [1][2][3]. It is one of the most extensively used FAAH inhibitor research tools.

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Cannabinoid

WIN 55,212-2

WIN 55,212-2 is a synthetic aminoalkylindole cannabinoid receptor agonist that binds and fully activates both the CB1 and CB2 cannabinoid receptors, and is one of the most widely used reference agonists in endocannabinoid pharmacology. Developed by Sterling Winthrop from the aminoalkylindole (pravadoline) series while researchers were pursuing non-steroidal anti-inflammatory analgesics, it is structurally unrelated to plant-derived cannabinoids like THC yet produces overlapping in vivo effects including antinociception, hypothermia, catalepsy and hypomotility. It is a laboratory tool compound rather than an approved medicine, valued because it is a high-potency full agonist with slight CB2 preference and because its two enantiomers (the active R(+) form versus the near-inactive S(-) WIN 55,212-3) allow clean stereochemical control experiments. It has no approved medical use and is a Schedule I controlled substance in many jurisdictions as a synthetic cannabinoid.

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