The discovery of cannabinoid receptors (CBs) and their putative ligands (i.e. endocannabinoids) less than twenty years ago has open the way for the identification of a plastic innate signalling system, better known as the Endocannabinoid System (ES), involved in many (patho)physiological functions. Thus, there has been a growing interest in the development of new compounds that selectively regulate and/or modify the action and the levels of these lipid mediators. During our research in the cannabinoid field, we have designed and developed an attractive medicinal chemistry template (Brizzi et al., J.Med. Chem. 2005; 48:7343-7350) which turned out to produce potent cannabimimetic ligands. In our previous studies, we have also assessed the influence of both the alkyloxy chain (Brizzi et al., Bioorg. Med. Chem. 2007, 15:5406-5416) and the alkyl tail on the cannabinoid receptor affinity (Brizzi et al., J. Med. Chem. 2009, 52:2506-2514). In order to validate our resorcinol-hybrid model, we have synthesized a novel series of compounds characterized by an amide head with different electronic properties or a glycerol-ester/glycerol-ether head. Methods:The synthetic pathway started from properly substituted phenols (i.e.olivetol, 5-(2-methyloctan-2-yl)resorcinol, 4-hexylresorcinol) which were alkylated with bromoalkyl acid methyl esters and/or bromoalkyl glycerol-esters/ethers in dry acetone in the presence of anhydrous potassium carbonate and potassium fluoride to furnish the corresponding esters/ethers in moderate to good yield. Final amides were synthesized reacting the corresponding acid, obtained from hydrolysis of esters with methanolic/aqueous sodium hydroxide solution, with the appropriate amines in the presence of different condensing agents. Glycerol-derivatives were obtained by cleavage of the benzylidene and acetonide protecting groups with acids. All the newly synthesized compounds were evaluated for their affinity at recombinant human CB1 and CB2 receptors over-expressed in COS cells. Results: 1) Amide head must be of little steric hindrance; 2) Substitution of the amide by an ester head was well tolerated, giving potent CB1 ligands; 3) Inversion of the amide head caused a decrease or a loss of the receptor activity; 4) Replacement of the carbonyl functionality with a methylene group (ether linkage) proved to be detrimental for cannabinoid receptor interaction. Conclusions: Analysis of the binding assay results was very complex and multifaceted. The carbonyl group seemed to play a crucial role in the cannabinoid receptor interaction and these resorcinol hybrids appeared to be very sensitive to structural changes in the amide moiety.
A structure-affinity study on new resorcinol “hybrids”: role of the amide head on the cannabinoid receptor interaction
AIELLO, Francesca;
2011-01-01
Abstract
The discovery of cannabinoid receptors (CBs) and their putative ligands (i.e. endocannabinoids) less than twenty years ago has open the way for the identification of a plastic innate signalling system, better known as the Endocannabinoid System (ES), involved in many (patho)physiological functions. Thus, there has been a growing interest in the development of new compounds that selectively regulate and/or modify the action and the levels of these lipid mediators. During our research in the cannabinoid field, we have designed and developed an attractive medicinal chemistry template (Brizzi et al., J.Med. Chem. 2005; 48:7343-7350) which turned out to produce potent cannabimimetic ligands. In our previous studies, we have also assessed the influence of both the alkyloxy chain (Brizzi et al., Bioorg. Med. Chem. 2007, 15:5406-5416) and the alkyl tail on the cannabinoid receptor affinity (Brizzi et al., J. Med. Chem. 2009, 52:2506-2514). In order to validate our resorcinol-hybrid model, we have synthesized a novel series of compounds characterized by an amide head with different electronic properties or a glycerol-ester/glycerol-ether head. Methods:The synthetic pathway started from properly substituted phenols (i.e.olivetol, 5-(2-methyloctan-2-yl)resorcinol, 4-hexylresorcinol) which were alkylated with bromoalkyl acid methyl esters and/or bromoalkyl glycerol-esters/ethers in dry acetone in the presence of anhydrous potassium carbonate and potassium fluoride to furnish the corresponding esters/ethers in moderate to good yield. Final amides were synthesized reacting the corresponding acid, obtained from hydrolysis of esters with methanolic/aqueous sodium hydroxide solution, with the appropriate amines in the presence of different condensing agents. Glycerol-derivatives were obtained by cleavage of the benzylidene and acetonide protecting groups with acids. All the newly synthesized compounds were evaluated for their affinity at recombinant human CB1 and CB2 receptors over-expressed in COS cells. Results: 1) Amide head must be of little steric hindrance; 2) Substitution of the amide by an ester head was well tolerated, giving potent CB1 ligands; 3) Inversion of the amide head caused a decrease or a loss of the receptor activity; 4) Replacement of the carbonyl functionality with a methylene group (ether linkage) proved to be detrimental for cannabinoid receptor interaction. Conclusions: Analysis of the binding assay results was very complex and multifaceted. The carbonyl group seemed to play a crucial role in the cannabinoid receptor interaction and these resorcinol hybrids appeared to be very sensitive to structural changes in the amide moiety.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
