GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB₁ and CB₂ receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [11].

All listed agonists are putative endogenous agoists.

GPR18 failed to respond to a variety of lipid-derived agents in an in vitro screen [13], but has recently been reported to be activated by Δ⁹-tetrahydrocannabinol [6]. GPR55 responds to AM251 and rimonabant at micromolar concentrations, compared to their nanomolar affinity as CB₁ receptor antagonists/inverse agonists [11]. It has been reported lysophosphatidylinositol acts at other sites [1]. It has also been suggested oleoyl-lysophosphatidylcholine acts, at least in part, through GPR119 [7]. Although PSN375963 and PSN632408 produce GPR119-dependent responses in heterologous expression systems, comparison with oleoylethanolamide-mediated responses suggests additional mechanisms of action [7].

Bradshaw, HB; Lee, SH; McHugh, D. (2009) Orphan endogenous lipids and orphan GPCRs: a good match. Prostaglandins Other Lipid Mediat., 89 (3-4): 131-4. [PMID:19379823]

Godlewski, G; Offertáler, L; Wagner, JA; Kunos, G. (2009) Receptors for acylethanolamides-GPR55 and GPR119. Prostaglandins Other Lipid Mediat., 89 (3-4): 105-11. [PMID:19615459]

Hansen, HS; Diep, TA. (2009) N-acylethanolamines, anandamide and food intake. Biochem. Pharmacol., 78 (6): 553-60. [PMID:19413995]

Pertwee, RG; Howlett, AC; Abood, ME; Alexander, SP; Di Marzo, V; Elphick, MR; Greasley, PJ; Hansen, HS; Kunos, G; Mackie, K; et al.. (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol. Rev., 62 (4): 588-631. [PMID:21079038]

Ross, RA. (2011) L-α-lysophosphatidylinositol meets GPR55: a deadly relationship. Trends Pharmacol. Sci., 32 (5): 265-9. [PMID:21367464]

Sharir, H; Abood, ME. (2010) Pharmacological characterization of GPR55, a putative cannabinoid receptor. Pharmacol. Ther., 126 (3): 301-13. [PMID:20298715]

1. Bondarenko, AI; Malli, R; Graier, WF. (2011) The GPR55 agonist lysophosphatidylinositol acts as an intracellular messenger and bidirectionally modulates Ca2+ -activated large-conductance K+ channels in endothelial cells. Pflugers Arch., 461 (1): 177-89. [PMID:21072666]

2. Chu, ZL; Carroll, C; Chen, R; Alfonso, J; Gutierrez, V; He, H; Lucman, A; Xing, C; Sebring, K; Zhou, J; et al.. (2010) N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119. Mol. Endocrinol., 24 (1): 161-70. [PMID:19901198]

3. Henstridge, CM; Balenga, NA; Schröder, R; Kargl, JK; Platzer, W; Martini, L; Arthur, S; Penman, J; Whistler, JL; Kostenis, E; Waldhoer, M; Irving, AJ. (2010) GPR55 ligands promote receptor coupling to multiple signalling pathways. Br. J. Pharmacol., 160 (3): 604-14. [PMID:20136841]

4. Kapur, A; Zhao, P; Sharir, H; Bai, Y; Caron, MG; Barak, LS; Abood, ME. (2009) Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. J. Biol. Chem., 284 (43): 29817-27. [PMID:19723626]

5. Kohno, M; Hasegawa, H; Inoue, A; Muraoka, M; Miyazaki, T; Oka, K; Yasukawa, M. (2006) Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem. Biophys. Res. Commun., 347 (3): 827-32. [PMID:16844083]

6. McHugh, D; Page, J; Dunn, E; Bradshaw, HB. (2011) Δ(9) -THC and N-arachidonyl glycine are full agonists at GPR18 and cause migration in the human endometrial cell line, HEC-1B. Br J Pharmacol,  [Epub ahead of print]. [PMID:21595653]

7. Ning, Y; O'Neill, K; Lan, H; Pang, L; Shan, LX; Hawes, BE; Hedrick, JA. (2008) Endogenous and synthetic agonists of GPR119 differ in signalling pathways and their effects on insulin secretion in MIN6c4 insulinoma cells. Br. J. Pharmacol., 155 (7): 1056-65. [PMID:18724386]

8. Oka, S., Nakajima, K., Yamashita, A., Kishimoto, S. and Suqiura, T. (2007) Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun, 362 (4): 928-934. [PMID:17765871]

9. Oka, S., Toshida, T., Maruyama, K., Nakajima, K., Yamashita, A. and Sugiura, T. (2009) 2-Arachidonoyl-sn-glycero-3-phosphoinositol: A Possible Natural Ligand for GPR55. J Biochem, 145 (1): 13-20. [PMID:18845565]

10. Overton, H. A., Babbs, A. J., Doel, S. M., Fyfe, M. C., Gardner, L. S., Griffin, G., Jackson, H. C., Procter, M. J., Rasamison, C. M., Tang-Christensen, M., Widdowson, P. S., Williams, G. M. and Reynet, C. (2006) Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab, 3: 167-175. [PMID:16517404]

11. Pertwee, RG; Howlett, AC; Abood, ME; Alexander, SP; Di Marzo, V; Elphick, MR; Greasley, PJ; Hansen, HS; Kunos, G; Mackie, K; et al.. (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol. Rev., 62 (4): 588-631. [PMID:21079038]

12. Ryberg, E., Larsson, N., Sjögren, S., Hjorth, S., Hermansson, N.O., Leonova, J., Elebring, T., Nilsson, K., Drmota, T. and Greasley, P.J. (2007) The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol, 152: 1092-1101. [PMID:17876302]

13. Yin, H., Chu, A., Li, W., Wang, B., Shelton, F., Otero, F., Nguyen, D.G., Caldwell, J.S. and Chen, Y.A. (2009) Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay. J Biol Chem, 284: 12328-12338. [PMID:19286662]

14. Yoshida, S; Ohishi, T; Matsui, T; Shibasaki, M. (2010) Identification of a novel GPR119 agonist, AS1269574, with in vitro and in vivo glucose-stimulated insulin secretion. Biochem. Biophys. Res. Commun., 400 (3): 437-41. [PMID:20804735]