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Molecular Pharmacology

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Abstract

Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid.

J C Pinto, F Potié, K C Rice, D Boring, M R Johnson, D M Evans, G H Wilken, C H Cantrell and A C Howlett
Molecular Pharmacology September 1994, 46 (3) 516-522;
J C Pinto
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F Potié
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K C Rice
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D Boring
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M R Johnson
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D M Evans
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G H Wilken
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C H Cantrell
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A C Howlett
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Abstract

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.

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Molecular Pharmacology
Vol. 46, Issue 3
1 Sep 1994
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Abstract

Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid.

J C Pinto, F Potié, K C Rice, D Boring, M R Johnson, D M Evans, G H Wilken, C H Cantrell and A C Howlett
Molecular Pharmacology September 1, 1994, 46 (3) 516-522;

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Abstract

Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid.

J C Pinto, F Potié, K C Rice, D Boring, M R Johnson, D M Evans, G H Wilken, C H Cantrell and A C Howlett
Molecular Pharmacology September 1, 1994, 46 (3) 516-522;
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