N-Acyl Amino Acids (Elmiric Acids): Endogenous Signaling Molecules with Therapeutic Potential

The subject of N-acyl amino acid conjugates has been rapidly growing in recent years, especially with regard to their analgesic and anti-inflammatory actions. The field comprises a large family of lipid signaling molecules whose importance is only now being fully realized. The most widely studied member is N-arachidonoyl glycine (NAGly), which differs structurally from the endocannabinoid anandamide (N-arachidonoyl ethanolamide) by a single oxygen atom even as the two are metabolically related. Topics that are covered in this minireview are: biosynthetic pathways for N-acyl amino acids, receptors for N-acyl amino acids, physiologic actions of N-acyl amino acids, pharmacological effects of N-acyl amino acids, and molecular mechanisms believed to be responsible for their effects. On the subject of mechanisms, we propose several possibilities whose basis is the currently available information. Four putative pathways can be suggested: 1) inhibition of fatty acid amide hydrolase-induced increases in anandamide or 2-arachidonoyl glycerol (2-AG) levels, resulting in analgesic activity; 2) binding to GPR18, initiating the production of anti-inflammatory eicosanoids (specifically, the data suggest roles for 15-deoxy-Δ^12,14-prostaglandin-J₂ and lipoxin A₄, both of which are potent inflammation-resolving molecules); 3) inactivation of T-type Cav3 channels; and 4) inhibition of the GLYT2 glycine transporter. Each pathway would produce analgesic effects. Also, the N-acyl amino acids do not bind to either cannabinoid or opioid receptors, thus reducing adverse actions and making them good templates for novel drug candidate molecules.