N-acyl amino acids and N-acyl neurotransmitter conjugates: neuromodulators and probes for new drug targets

Abstract

The myriad functions of lipids as signalling molecules is one of the most interesting fields in contemporary pharmacology, with a host of compounds recognized as mediators of communication within and between cells. The N-acyl conjugates of amino acids and neurotransmitters (NAANs) have recently come to prominence because of their potential roles in the nervous system, vasculature and the immune system. NAAN are compounds such as glycine, GABA or dopamine conjugated with long chain fatty acids. More than 70 endogenous NAAN have been reported although their physiological role remains uncertain, with various NAAN interacting with a low affinity at G protein coupled receptors (GPCR) and ion channels. Regardless of their potential physiological function, NAAN are of great interest to pharmacologists because of their potential as flexible tools to probe new sites on GPCRs, transporters and ion channels. NAANs are amphipathic molecules, with a wide variety of potential fatty acid and headgroup moieties, a combination which provides a rich source of potential ligands engaging novel binding sites and mechanisms for modulation of membrane proteins such as GPCRs, ion channels and transporters. The unique actions of subsets of NAAN on voltage-gated calcium channels and glycine transporters indicate that the wide variety of NAAN may provide a readily exploitable resource for defining new pharmacological targets. Investigation of the physiological roles and pharmacological potential of these simple lipid conjugates is in its infancy, and we believe that there is much to be learnt from their careful study.

Figure 1

Structures of N-acyl amino acid/neurotransmitter (NAAN). The prototypical NAAN, N-arachidonoyl glycine (NA-Gly) is shown with the tail and head groups circled. The various NAAN differ in the length and degree of saturation of the hydrophobic acyl tail group. NA-Gly is closely related to anandamide, with the only difference being that NA-Gly has a carboxyl group compared with a hydroxyl group on anandamide. Other amino acid or neurotransmitter head groups are also shown.

Figure 2

Potential sites of action for N-acyl amino acid/neurotransmitter (NAAN) on receptors, channels and transporters. A variety of sites has been proposed for NAAN binding to membrane proteins, some possible ones are illustrated here. Very little is known about NAAN interactions with G protein coupled receptors (GPCRs), but some possibilities are that the NAAN may disrupt lipid packing at the GPCR-lipid interface and alter the dynamics of protein signaling. The head group may provide specificity, while the lipid tail may alter membrane dynamics. Both inhibitory and stimulatory binding sites have been proposed for Ca²⁺ channels. NAAN may diffuse through the membrane to interact with intracellular binding sites of ion channels and alter the kinetics of channel function. NAAN may bind to extracellular recognition sites of transporters and alter the conformational changes associated with the transport process.