CB1: 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

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

JZL195

JZL195 is a first-in-class, centrally active dual inhibitor of the two principal endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), reported with in vitro IC50 values of approximately 2 nM and 4 nM respectively [1]. By simultaneously blocking both catabolic pathways it raises brain and peripheral levels of the two major endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), thereby driving broad, indirect activation of the cannabinoid CB1 receptor [1]. It is a research chemical used to dissect endocannabinoid signalling and is not an approved human medicine.

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Sleep Support

Oleamide

Oleamide (cis-9,10-octadecenoamide) is an endogenous fatty acid primary amide, the simple amide of oleic acid, and the prototypical member of a family of brain lipids that function as biological signaling molecules [1]. It first drew attention when it was isolated from the cerebrospinal fluid of sleep-deprived cats, where it accumulates in proportion to the sleep debt and, when injected into rats, induces physiological sleep [1]. Mechanistically it is a substrate of fatty acid amide hydrolase (FAAH), the same enzyme that degrades the endocannabinoid anandamide, and it modulates cannabinoid, serotonergic, GABAergic, and gap-junction signaling [2][3][4][5]. In the supplement market it is sold as a sleep and relaxation aid, although controlled human evidence remains thin and most of what is known derives from cell and rodent work [6][13].

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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

Tetrahydrocannabiphorol

Tetrahydrocannabiphorol (THCP) is a naturally occurring phytocannabinoid that shares the core structure of Δ⁹-tetrahydrocannabinol (THC) but carries a seven-carbon (heptyl) alkyl side chain rather than the five-carbon (pentyl) chain of THC. It was first isolated and characterized in 2019 from the Italian medicinal cannabis variety FM2 by Citti, Cannazza and colleagues [1]. The extended side chain confers markedly higher binding affinity at the cannabinoid CB1 receptor, with a reported inhibition constant near 1.2 nM, roughly a factor of thirty greater than that of THC, and this affinity is comparable to the potent synthetic full agonist CP55940 [1]. In the classic cannabinoid tetrad in mice, THCP reproduced the THC-like profile of hypomotility, analgesia, catalepsy and hypothermia at lower doses than THC, indicating high in vivo cannabimimetic potency [1]. THCP occurs in cannabis only in trace amounts and now appears widely in unregulated consumer products, prompting active work on its detection, metabolism and safety [3][6][7][8].

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Cannabinoid

Tetrahydrocannabivarin

Tetrahydrocannabivarin (THCV) is a naturally occurring, minor phytocannabinoid found in Cannabis sativa and the propyl homologue of delta-9-tetrahydrocannabinol (THC), differing only in a shortened three-carbon side chain [1][2]. It is pharmacologically distinct from THC: at low doses it behaves as a cannabinoid CB1 receptor antagonist that tends to suppress appetite, while at higher doses it can act as a CB1 agonist, and it is separately a high-affinity partial agonist at CB2 receptors [1][3]. Preclinical work and a small human trial point to benefits in glycaemic control, energy metabolism, neuroprotection and neuroinflammation, which has fuelled its reputation as a metabolically favourable, non-appetite-stimulating cannabinoid [4][5][6].

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