roup) attached to a simple amine by an amide link where amines can be substituted by amino acids or their byproducts, if they can be conjugated with a fatty acid \[[@B65-ijms-21-03421]\].

N-acyl amides are considered "orphan lipids", since no specific receptor for these molecules has been discovered; nevertheless, there is evidence of their ability to bind to different endocannabinoid receptors including CB1 and CB2, to G-protein-coupled receptors (GPCRs) 18 and 55 (GPR18 and 55), and to some members of the TRP ion channel family \[[@B65-ijms-21-03421]\].

In 2014, Bradshaw and collaborators reported different N-acyl amides as activators of TRP ion channels (TRPV1-V4). Using an internal library of 70 N-acyl amides and measurements of changes in intracellular Ca^2+^ levels through fluorescent ratiometric indicators (i.e., Fura-2 AM), these authors identified several agonists of the TRPV1 channel \[[@B66-ijms-21-03421]\] ([Figure 4](#ijms-21-03421-f004){ref-type="fig"}).

Other molecules such as N-acyl GABA and similar compounds such as N-docosahexaenoyl GABA (D-GABA), N-linoleoyl GABA (L-GABA), and N-arachidonoyl GABA (A-GABA) also resulted in Ca^2+^ mobilization into the cell in a concentration-dependent fashion. In addition to N-acyl GABA and its derivatives, five other N-acyl amides that were more efficient in activating TRPV1 were identified: N-docosahexaenoyl ethanoyl serine, N-docosahexaenoyl glycine, N-docosahexaenoyl aspartic acid, N-docosahexaenoyl ethanolamide, and N-linoleoyl ethanolamide \[[@B66-ijms-21-03421]\] ([Figure 4](#ijms-21-03421-f004){ref-type="fig"}). In summary, by testing several biologically active lipids, the authors concluded that long-chain unsaturated acyl amides function as TRPV1 activators. Nonetheless, work still needs to be performed to determine the mechanisms by which these molecules modulate the function of TRPV1 and establish binding sites for these in the ion channel.

### 3.2.2. N-Acylethanolamines {#sec3dot2dot2-ijms-21-03421}

N-Acylethanolamines *(NAEs)* are lipids which