Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oleamide is an endogenous fatty acid primary amide that accumulates in the cerebrospinal fluid under conditions of sleep deprivation and induces physiological sleep in animals. A review covering its discovery, its implications, and the emerging biology surrounding its discovery is presented. Consistent with its role as a prototypical member of a new class of biological signaling molecules, enzymatic regulation of endogenous concentrations of oleamide have been characterized or proposed. Fatty acid amide hydrolase (FAAH) is an integral membrane protein that degrades oleamide and potent inhibitors with physiological sleep-inducing properties have been disclosed. The characterization, cloning, and neuronal distribution of FAAH have been detailed and the enzyme was found to possess the ability to hydrolyze a range of fatty acid amides including anandamide which serves as the endogenous ligand for the cannabinoid receptor. An additional endogenous substance with REM sleep-inducing properties, 2-octyl gamma-bromoacetoacetate, was characterized as a potent FAAH inhibitor. Oleamide has been shown to modulate serotonergic neurotransmission and inhibit intercellular gap junction communication and detailed studies of its well defined and selective structural features required for activity have been disclosed.
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PMID:Oleamide: an endogenous sleep-inducing lipid and prototypical member of a new class of biological signaling molecules. 1019 45

Structure-activity relation studies have established that the alkyl side chain in tetrahydrocannabinol (THC) plays a crucial role in the activation of the cannabinoid receptor. Unfortunately, the flexible nature of this side chain has hampered efforts to elucidate the precise nature of the interaction of THC with its receptors. Therefore, a series of analogs with structurally restrained side chains of varying length was synthesized and evaluated for pharmacological potency in mice and for receptor affinity. The introduction of cis double bonds inserted rigid angles, whereas triple bonds developed regions of planarity. Receptor affinity for the acetylenic and saturated side chains were the same, whereas double bond substitution increased affinity 10-fold. Moreover, the relationship between receptor affinity and potency was 10-fold less than that of Delta(8)-THC in the case of some acetylenic derivatives, whereas changing the triple bond to a double bond restored the potency/affinity ratio. Additionally, an acetylene at C2-C3 in the octyl and nonyl side chains favored antinociception by as much as 70-fold. Surprisingly, several high-affinity acetylenic derivatives, especially those with cyano substitutions at the terminus of the side chain, were partial agonists or were inactive. Some of these low-efficacy, high-affinity ligands elicited antagonistic activity. The finding that manipulations of the side chain produces high- affinity ligands with either antagonist, partial agonist, or full agonist effects reveals a critical structural feature for receptor activation.
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PMID:Manipulation of the tetrahydrocannabinol side chain delineates agonists, partial agonists, and antagonists. 1045 79

1. We have extended previous investigations of four analogues of Delta8-tetrahydrocannabinol (Delta8-THC): 6'-azidohex-2'-yne-Delta8-THC (O-1184), 6'-azidohex-cis-2'-ene-Delta8-THC (O-1238) and octyl-2'-yne-Delta8-THC (O-584) and its 1-deoxy-analogue (O-1315). 2. O-1184, O-1238 and O-584 displaced [3H]-CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell membranes expressing CB1 or CB2 cannabinoid receptors, with pKi values of 8.28 to 8.45 (CB1) and 8.03 to 8.13 (CB2). The pKi values of O-1315 were significantly less, 7.63 (CB1) and 7.01 (CB2). 3. All the analogues inhibited forskolin-stimulated cyclic AMP production by CB1-transfected CHO cells (pEC50=9.16 to 9.72). Only O-1238 behaved as a full agonist in this cell line. 4. In mouse vasa deferentia, O-1238 inhibited electrically-evoked contractions (pEC50=10.18 and Emax=70.5%). Corresponding values for O-1184 were 9.08 and 21.1% respectively. At 1 nM, O-1184 produced surmountable antagonism of the cannabinoid receptor agonist, CP55940. However, at 0.1 nM, O-1184 did not attenuate CP55940-induced inhibition of cyclic AMP production by CB1-transfected CHO cells. 5. In CB2-transfected CHO cells, cyclic AMP production was inhibited by CP55940 (pEC50=8.59), enhanced by O-1184 and O-584 (pEC50=8.20 and 6.86 respectively) and not significantly affected by O-1238 or O-1315. 6. At 100 nM, O-1184 and O-1238 produced surmountable antagonism of CP55940 in CB2 cells, decreasing the pEC50 of CP55940 from 8.61 to 7.42 (O-1184) or from 8. 54 to 7.44 (O-1238). 7. These data support the hypothesis that increasing the degree of unsaturation of the aliphatic side-chain of Delta8-THC analogues has little effect on CB1 or CB2 receptor affinity but can reduce CB1 receptor efficacy and reverse the direction of responses elicited at CB2 receptors.
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PMID:Structural determinants of the partial agonist-inverse agonist properties of 6'-azidohex-2'-yne-delta8-tetrahydrocannabinol at cannabinoid receptors. 1051 56