GPR35 as a Novel Therapeutic Target

Abstract

G protein-coupled receptors (GPCRs) remain the best studied class of cell surface receptors and the most tractable family of proteins for novel small molecule drug discovery. Despite this, a considerable number of GPCRs remain poorly characterized and in a significant number of cases, endogenous ligand(s) that activate them remain undefined or are of questionable physiological relevance. GPR35 was initially discovered over a decade ago but has remained an “orphan” receptor. Recent publications have highlighted novel ligands, both endogenously produced and synthetic, which demonstrate significant potency at this receptor. Furthermore, evidence is accumulating which highlights potential roles for GPR35 in disease and therefore, efforts to characterize GPR35 more fully and develop it as a novel therapeutic target in conditions that range from diabetes and hypertension to asthma are increasing. Recently identified ligands have shown marked species selective properties, indicating major challenges for future drug development. As we begin to understand these issues, the continuing efforts to identify novel agonist and antagonist ligands for GPR35 will help to decipher its true physiological relevance; translating multiple assay systems in vitro, to animal disease systems in vivo and finally to man.

Antagonists of GPR35 Display High Species Ortholog Selectivity and Varying Modes of Action

“…In recent times the poorly characterized GPCR GPR35 has been suggested to be a potential therapeutic target in areas ranging from diabetes, cardiovascular disease, and inflammation to pain (MacKenzie et al, 2011;Milligan, 2011). In part, this has been based simply on the expression patterns of GPR35.…”

“…GPR35 is a poorly characterized member of the rhodopsinlike, class A subfamily of G protein-coupled receptors (GPCRs), which, based in part on expression pattern, has attracted attention as a possible therapeutic target in conditions ranging from diabetes and cardiovascular disease to inflammation and pain (MacKenzie et al, 2011;Milligan, 2011). There are, however, major challenges in efforts to understand the role of this receptor.…”

“…These include that kynurenic acid, the first endogenously produced molecule identified as being able to activate GPR35 (Wang et al, 2006), is substantially more potent at the rat ortholog than the human form (Jenkins et al, 2010). This has resulted in suggestions that kynurenic acid may not be a true endogenous regulator of at least the human ortholog, leaving GPR35 as an "orphan" receptor (MacKenzie et al, 2011). Although a number of synthetic GPR35 agonists have been identified via various screens (Jenkins et al, 2010;Zhao et al, 2010), some of them also display marked variations in potency to activate the human and rat orthologs (Jenkins et al, 2010;Milligan, 2011).…”

The Antiallergic Mast Cell Stabilizers Lodoxamide and Bufrolin as the First High and Equipotent Agonists of Human and Rat GPR35

“…Although poorly characterized, the seven transmembrane domain (TMD), G protein-coupled receptor (GPCR) GPR35 has attracted attention as a potential therapeutic target in disease areas ranging from pain to hypertension (MacKenzie et al, 2011;Milligan, 2011). Although GPR35 is indicated to be a receptor responsive to the endogenously produced tryptophan metabolite kynurenic acid (Wang et al, 2006), lack of convergence on this issue has resulted in a number of efforts to identify surrogate agonist ligands that might be used to help further define the roles of this receptor.…”

The emerging pharmacology and function of GPR35 in the nervous system

“…GPR35 is a poorly characterised, 7-transmembrane domain, GPCR that transmits function 50 via interaction with Gα i/o , Gα 13 , and ² -arrestin (Figure 1) (Milligan, 2011;Mackenzie et al, 2011; 51 Divorty et al, 2015; Shore and Reggio, 2015). In terms of sequence similarity, GPR35 is related to 52 the purinergic receptor LPA 4 (32 %), the hydroxycarboxylic acid binding receptors HCA 2 and HCA 3 53 (30 %), and the cannabinoid and lysophosphatidylinositol-binding GPR55 receptor (30 %) (O'Dowd 54 et al, 1998).…”