(R)-Methanandamide : a chiral novel anandamide possessing higher potency and metabolic stability

V Abadji, S Y Lin, G Taha, G Griffin, Lesley Ann Stevenson, Roger Guy Pertwee, A Makriyannis

Research output: Contribution to journalComment/debate

295 Citations (Scopus)

Abstract

Four chiral congeners of arachidonylethanolamide (anandamide) have been synthesized and evaluated for (a) their ability to bind to the cannabinoid receptor in rat forebrain membranes and (b) their pharmacological potency as measured by the compounds' ability to inhibit electrically-evoked contractions of the mouse vas deferens. The lead analog was also tested for its potency in. vivo. Of the analogs tested, (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide [(R)-methanandamide] exhibited the highest affinity for the cannabinoid receptor with a K-i of 20 +/- 1.6 nM, 4-fold lower than that of anandamide (K-i = 78 +/- 2 nM). Moreover, determination of the cannabinoid binding affinity in the presence and absence of the protease inhibitor phenylmethanesulfonyl fluoride (PMSF) revealed that (R)-methanandamide possesses a remarkable stability to aminopeptidase hydrolysis. Pharmacological studies on mouse isolated vasa deferentia demonstrated that all four analogs produce concentration-related inhibition of the twitch response and the order of potency is the same as the rank order of the affinities of these agonists for cannabinoid binding sites. Furthermore, experiments with mice have demonstrated that (R)-methanandamide also possesses cannabimimetric properties in vivo, as established by the four tests of hypothermia, hypokinesia, ring immobility, and antinociception.

Original languageEnglish
Pages (from-to)1889-1893
Number of pages5
JournalJournal of Medicinal Chemistry
Volume37
Issue number12
DOIs
Publication statusPublished - 10 Jun 1994

Keywords

  • CANNABINOID RECEPTOR AGONIST
  • CANNABIMIMETIC AGENTS
  • BRAIN CONSTITUENT
  • ANALOGS
  • BINDS
  • cannabinoid receptor agonist
  • cannabinimetic agents
  • brain constituent
  • analogs
  • binds

Cite this

(R)-Methanandamide : a chiral novel anandamide possessing higher potency and metabolic stability. / Abadji, V ; Lin, S Y ; Taha, G ; Griffin, G ; Stevenson, Lesley Ann; Pertwee, Roger Guy; Makriyannis, A .

In: Journal of Medicinal Chemistry, Vol. 37, No. 12, 10.06.1994, p. 1889-1893.

Research output: Contribution to journalComment/debate

Abadji, V ; Lin, S Y ; Taha, G ; Griffin, G ; Stevenson, Lesley Ann ; Pertwee, Roger Guy ; Makriyannis, A . / (R)-Methanandamide : a chiral novel anandamide possessing higher potency and metabolic stability. In: Journal of Medicinal Chemistry. 1994 ; Vol. 37, No. 12. pp. 1889-1893.
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abstract = "Four chiral congeners of arachidonylethanolamide (anandamide) have been synthesized and evaluated for (a) their ability to bind to the cannabinoid receptor in rat forebrain membranes and (b) their pharmacological potency as measured by the compounds' ability to inhibit electrically-evoked contractions of the mouse vas deferens. The lead analog was also tested for its potency in. vivo. Of the analogs tested, (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide [(R)-methanandamide] exhibited the highest affinity for the cannabinoid receptor with a K-i of 20 +/- 1.6 nM, 4-fold lower than that of anandamide (K-i = 78 +/- 2 nM). Moreover, determination of the cannabinoid binding affinity in the presence and absence of the protease inhibitor phenylmethanesulfonyl fluoride (PMSF) revealed that (R)-methanandamide possesses a remarkable stability to aminopeptidase hydrolysis. Pharmacological studies on mouse isolated vasa deferentia demonstrated that all four analogs produce concentration-related inhibition of the twitch response and the order of potency is the same as the rank order of the affinities of these agonists for cannabinoid binding sites. Furthermore, experiments with mice have demonstrated that (R)-methanandamide also possesses cannabimimetric properties in vivo, as established by the four tests of hypothermia, hypokinesia, ring immobility, and antinociception.",
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T2 - a chiral novel anandamide possessing higher potency and metabolic stability

AU - Abadji, V

AU - Lin, S Y

AU - Taha, G

AU - Griffin, G

AU - Stevenson, Lesley Ann

AU - Pertwee, Roger Guy

AU - Makriyannis, A

PY - 1994/6/10

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N2 - Four chiral congeners of arachidonylethanolamide (anandamide) have been synthesized and evaluated for (a) their ability to bind to the cannabinoid receptor in rat forebrain membranes and (b) their pharmacological potency as measured by the compounds' ability to inhibit electrically-evoked contractions of the mouse vas deferens. The lead analog was also tested for its potency in. vivo. Of the analogs tested, (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide [(R)-methanandamide] exhibited the highest affinity for the cannabinoid receptor with a K-i of 20 +/- 1.6 nM, 4-fold lower than that of anandamide (K-i = 78 +/- 2 nM). Moreover, determination of the cannabinoid binding affinity in the presence and absence of the protease inhibitor phenylmethanesulfonyl fluoride (PMSF) revealed that (R)-methanandamide possesses a remarkable stability to aminopeptidase hydrolysis. Pharmacological studies on mouse isolated vasa deferentia demonstrated that all four analogs produce concentration-related inhibition of the twitch response and the order of potency is the same as the rank order of the affinities of these agonists for cannabinoid binding sites. Furthermore, experiments with mice have demonstrated that (R)-methanandamide also possesses cannabimimetric properties in vivo, as established by the four tests of hypothermia, hypokinesia, ring immobility, and antinociception.

AB - Four chiral congeners of arachidonylethanolamide (anandamide) have been synthesized and evaluated for (a) their ability to bind to the cannabinoid receptor in rat forebrain membranes and (b) their pharmacological potency as measured by the compounds' ability to inhibit electrically-evoked contractions of the mouse vas deferens. The lead analog was also tested for its potency in. vivo. Of the analogs tested, (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide [(R)-methanandamide] exhibited the highest affinity for the cannabinoid receptor with a K-i of 20 +/- 1.6 nM, 4-fold lower than that of anandamide (K-i = 78 +/- 2 nM). Moreover, determination of the cannabinoid binding affinity in the presence and absence of the protease inhibitor phenylmethanesulfonyl fluoride (PMSF) revealed that (R)-methanandamide possesses a remarkable stability to aminopeptidase hydrolysis. Pharmacological studies on mouse isolated vasa deferentia demonstrated that all four analogs produce concentration-related inhibition of the twitch response and the order of potency is the same as the rank order of the affinities of these agonists for cannabinoid binding sites. Furthermore, experiments with mice have demonstrated that (R)-methanandamide also possesses cannabimimetric properties in vivo, as established by the four tests of hypothermia, hypokinesia, ring immobility, and antinociception.

KW - CANNABINOID RECEPTOR AGONIST

KW - CANNABIMIMETIC AGENTS

KW - BRAIN CONSTITUENT

KW - ANALOGS

KW - BINDS

KW - cannabinoid receptor agonist

KW - cannabinimetic agents

KW - brain constituent

KW - analogs

KW - binds

U2 - 10.1021/jm00038a020

DO - 10.1021/jm00038a020

M3 - Comment/debate

VL - 37

SP - 1889

EP - 1893

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -