The Synthesis of N-Vanillyl-arachidonoyl-amide (Arvanil) and its Analogs: An Improved Procedure for the Synthesis of the Key Synthon Methyl 14-Hydroxy-(all-cis)-5,8,11-tetradecatrienoate

Dasse, O. A.; Mahadevan, Anu; Han, Luning; Martin, Billy R.; Marzo, Vincenzo Di; Razdan, Raj K.

doi:10.1016/s0040-4020(00)00877-2

Cited by 31 publications

(21 citation statements)

References 40 publications

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“…28 Bromination gave the propargyl bromide 12, which was then coupled with methyl hex-5-ynoate in the presence of CuI as catalyst to provide the diynoic acid methyl ester 13. 29,30 Partial reduction of the diyne over 'nickel boride' catalyst provided the diene 14. 31 Deprotection of the silyl ether, followed by treatment of the alcohol 15 with MsCl, Et 3 N gave the desired mesylate 16 in 26% overall yield.…”

Section: Chemistrymentioning

confidence: 99%

Novel, potent THC/anandamide (hybrid) analogs

Bourne¹,

Roy²,

Wiley³

et al. 2007

Bioorganic & Medicinal Chemistry

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The structure activity relationship (SAR) of the end pentyl chain in anandamide (AEA) has been established to be very similar to that of Δ 9 -tetrahydrocannabinol Δ 9 -THC). In order to broaden our understanding of the structural similarities between AEA and THC, hybrid structures 1-3 were designed. In these hybrids the aromatic ring of THC-DMH was linked to the AEA moiety through an ether linkage with the oxygen of the phenol of THC. Hybrid 1 (O-220) was found to have very high binding affinity to CB1 receptors (Ki = 8.5 nM), and it is interesting to note that the orientation of the side chain with respect to the oxygen in the phenol is the same as in THCs. To further explore the SAR in this series the terminal carbon of the side chain was modified by adding different substituents. Several such analogs were synthesized and tested for their CB1 and CB2 binding affinities and in vivo activity (tetrad tests). The details of the synthesis and the biological activity of these compounds are described.

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Section: Chemistrymentioning

confidence: 99%

Novel, potent THC/anandamide (hybrid) analogs

Bourne¹,

Roy²,

Wiley³

et al. 2007

Bioorganic & Medicinal Chemistry

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“…We propose that non-CB 1 receptors are also important in determining high activity in the mouse tetrad tests. O-1986, O-1988, and O-2094 were synthesized by treatment of the appropriate amines with the acid chloride of arachidonic acid as described by us previously (Dasse et al, 2000). The amines used for O-1988 and O-2094 were prepared by reductive amination procedures (Abdel-Magid et al, 1996) using 3-methoxy-4-hydroxybenzaldehyde/CH 3 NH 2 ⅐HCl/methanol/NaCNBH 4 for the former and 3-chloro-4-hydroxybenzaldehyde/ammonium acetate/NaCNBH 4 / methanol/mol.sieves 3A°for the latter.…”

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confidence: 99%

A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid

Marzo¹,

Griffin²,

Petrocellis³

et al. 2002

J Pharmacol Exp Ther

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Arvanil, a structural "hybrid" between the endogenous cannabinoid CB 1 receptor ligand anandamide and capsaicin, is a potent agonist for the capsaicin receptor VR 1 (vanilloid receptor type 1), inhibits the anandamide membrane transporter (AMT), and induces cannabimimetic responses in mice. Novel arvanil derivatives prepared by N-methylation, replacement of the amide with urea and thiourea moieties, and manipulation of the vanillyl group were evaluated for their ability to bind/activate CB 1 receptors, activate VR 1 receptors, inhibit the AMT and fatty acid amide hydrolase (FAAH), and produce cannabimimetic effects in mice. The compounds did not stimulate the CB 1 receptor. Methylation of the amide group decreased the activity at VR 1 , AMT, and FAAH. On the aromatic ring, the substitution of the 3-methoxy group with a chlorine atom or the lack of the 4-hydroxy group decreased the activity on VR 1 and AMT, but not the affinity for CB 1 receptors, and increased the capability to inhibit FAAH. The urea or thiourea analogs retained activity at VR 1 and AMT but exhibited little affinity for CB 1 receptors. The urea analog was a potent FAAH inhibitor (IC 50 ϭ 2.0 M). A water-soluble analog of arvanil, O-2142, was as active on VR 1 , much less active on AMT and CB 1 , and more potent on FAAH. All compounds induced a response in the mouse "tetrad", particularly those with EC 50 Ͻ10 nM on VR 1 . However, the most potent compound, N-NЈ-di-(3-chloro-4-hydroxy)benzylarachidonamide (O-2093, ED 50 ϳ0.04 mg/kg), did not activate VR 1 or CB 1 receptors. Our findings suggest that VR 1 and/or as yet uncharacterized receptors produce cannabimimetic responses in mice in vivo.

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“…The model dienes 9a–f were synthesized in a straightforward manner following a common strategy (Scheme 2). The diynes ( 13a–f ) were synthesized by a copper-promoted coupling of a 1-alkyne with the requisite propargyl halide 9,10. Lindlar hydrogenation using the more reactive Pd/BaSO 4 catalyst produced the desired non-conjugated dienes having the cis,cis configuration.…”

Section: Resultsmentioning

confidence: 99%

“…In the case of the t Bu-substituted diene ( 9f ), Pd/BaSO 4 was only effective in the reduction of one of the double bonds, presumably due to steric effects. In that case, the more reactive Ni P-2 was used as the hydrogenation catalyst 10. This approach produced the requisite non-conjugated dienes in good to moderate yields and with a purity required for these studies.…”

Section: Resultsmentioning

confidence: 99%

Substituent Effects on Regioselectivity in the Autoxidation of Nonconjugated Dienes

2009

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Free radical oxidation of several 1,4-dienes was carried out in the presence of variable concentrations of α-tocopherol to investigate the effect of diene structure on product distribution. Oxidations carried out at low tocopherol concentration gave only C-1 and C-5 conjugated diene hydroperoxides while higher concentrations of the antioxidant resulted in formation of substantial amounts of the non-conjugated C-3 diene hydroperoxide. Increasing size of the substituents at C-1 and C-5 of the diene favor kinetic products arising from oxygen addition at the nonconjugated position, C-3, of the pentadienyl radical intermediate. Substituents at C-1 or C-5 of the pentadienyl radical also have a significant effect on the regioselectivity of the conjugated diene hydroperoxides formed, larger substituents directing oxygen addition to the pentadienyl radical at the site of least steric hindrance. This trend is also observed in oxidations of ω-3 and ω-6 linolenate fatty acid esters. Groups at C-1 and C-5 of the diene can influence product distribution based upon a.) steric demand in the oxygen-radical reaction and b.) the influence of substituents on the rearrangement of the C-3 peroxyl radical to give conjugated diene products.

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The Synthesis of N-Vanillyl-arachidonoyl-amide (Arvanil) and its Analogs: An Improved Procedure for the Synthesis of the Key Synthon Methyl 14-Hydroxy-(all-cis)-5,8,11-tetradecatrienoate

Cited by 31 publications

References 40 publications

Novel, potent THC/anandamide (hybrid) analogs

Novel, potent THC/anandamide (hybrid) analogs

A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid

Substituent Effects on Regioselectivity in the Autoxidation of Nonconjugated Dienes

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