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Tytuł:
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Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid.
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Autorzy:
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Pinto JC; Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Potié F
Rice KC
Boring D
Johnson MR
Evans DM
Wilken GH
Cantrell CH
Howlett AC
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Źródło:
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Molecular pharmacology [Mol Pharmacol] 1994 Sep; Vol. 46 (3), pp. 516-22.
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Typ publikacji:
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Journal Article; Research Support, U.S. Gov't, P.H.S.
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Język:
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English
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Imprint Name(s):
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Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics
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MeSH Terms:
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Arachidonic Acids/*pharmacology
Receptors, Drug/*drug effects
Adenylyl Cyclase Inhibitors ; Adenylyl Cyclases/metabolism ; Amides/metabolism ; Animals ; Arachidonic Acids/metabolism ; Binding Sites ; Brain/drug effects ; Brain/metabolism ; Dose-Response Relationship, Drug ; Esters/metabolism ; In Vitro Techniques ; Rats ; Receptors, Cannabinoid ; Receptors, Drug/agonists ; Receptors, Drug/metabolism ; Structure-Activity Relationship
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Grant Information:
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K05-DA00182 United States DA NIDA NIH HHS; R01-DA03690 United States DA NIDA NIH HHS; R01-DA06912 United States DA NIDA NIH HHS
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Substance Nomenclature:
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0 (Adenylyl Cyclase Inhibitors)
0 (Amides)
0 (Arachidonic Acids)
0 (Esters)
0 (Receptors, Cannabinoid)
0 (Receptors, Drug)
EC 4.6.1.1 (Adenylyl Cyclases)
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Entry Date(s):
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Date Created: 19940901 Date Completed: 19941110 Latest Revision: 20151119
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Update Code:
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20240104
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PMID:
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7935333
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The cannabinoid receptor in brain (CB1) specifically binds delta 9-tetrahydrocannabinol, the predominant central nervous system-active component of marijuana. An eicosanoid found in brain, N-(2-hydroxyethyl)arachidonylamide (anandamide), binds to CB1 with similar affinity. This report considers structure-activity requirements for a series of novel amides and rigid hairpin conformations typified by N-(2-hydroxyethyl)prostaglandin amides, assayed with phenylmethylsulfonyl fluoride inactivation of esterases/amidases. Arachidonyl esters were 30-fold less potent than N-(2-hydroxyethyl)arachidonylamide, showing a rank order of potency of methyl = ethyl > propyl = isopropyl. Within the N-(hydroxyalkyl)arachidonylamide series, a one-carbon increase in chain length increased the potency 2-fold, but continued extension decreased affinity. Substituting the amide for the N-(2-hydroxyethyl)amide function produced a 4-fold loss of affinity. The N-(propyl)-, N-(butyl)-, and N-(benzyl)arachidonylamide derivatives exhibited a 3-fold increase, no change, and a 5-fold decrease, respectively, in affinity, compared with N-(2-hydroxyethyl)arachidonylamide. Both the methoxy ether and the formamide derivatives suffered > 20-fold loss of potency, compared with N-(2-hydroxyethyl)arachidonylamide. N-(2-Aminoethyl)arachidonylamide interacted poorly with CB1. At 100 microM, N-(2-hydroxyethyl)amide analogs of prostaglandin E2, A2, B2, and B1 failed to alter [3H]CP55940 binding to CB1. N-(2-Hydroxyethyl)arachidonylamide inhibited adenylate cyclase with lesser potency but with similar efficacy, compared with desacetyllevonantradol. Extending the length of the hydroxyalkyl moiety by one carbon increased the apparent potency by 1 order of magnitude. The N-(propyl) derivative exhibited a 5-fold greater potency than did the N-(2-hydroxyethyl) analog. It appears that the bulk and length of the moiety appended to arachidonic acid are more important determinants of affinity for CB1 than is hydrogen-bonding capability.