orphan gpcrs: an update

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  • 1.In memory of Anthony (Tony) John Harmar, FRSE 28 November 1951 10 April 2014

2. Orphan GPCRs: an update Adam J. Pawson Monday 14th July 2014,WCP2014 3. Background The Nomenclature Committee of IUPHAR (NC- IUPHAR; since 1992); The IUPHAR database (since 2000); In-depth coverage of the properties and pharmacology of G protein-coupled receptors (including orphans), voltage- and ligand-gated ion channels, and nuclear hormone receptors. 4. Updating the GPCR list 2005 2013 5. Orphan receptors An orphan receptor is an apparent receptor that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified; Examples of orphan receptors are found in the GPCR and nuclear receptor families; GPCR orphan receptors are usually given the name GPR followed by a number, e.g. GPR1. Status monitored by the Evolving Pharmacology Group (Chaired by Anthony Davenport); 6. Orphan receptors 7. Criteria for deorphanisation (1) Several criteria are used by NC-IUPHAR in considering the assignment of an endogenous ligand to a receptor; It is recognized that these criteria are exacting and are unlikely to be met in all instances; Reproducibility of orphan-ligand pairing is the minimum criterion; 8. Criteria for deorphanisation (2) Two or more refereed papers from independent research groups should demonstrate activity of the ligand at the receptor with a potency that is consistent with a physiologic function; Preferably, both radioligand binding and functional assays should be employed; both in vitro and in native tissues; 9. Criteria for deorphanisation (3) Selective agonists should mimic and selective antagonists should block the action of the putative endogenous ligand; The putative endogenous ligand should be present in tissues in appropriate concentrations; Receptor gene deletion (in mice) should abolish receptor characteristics (radioligand binding/ actions of ligand in functional assays); Receptor overexpression may be expected to potentiate these actions; 10. Additional considerations Lipids as putative endogenous orthosteric ligands for GPCRs pose distinct difficulties; Absence of endogenous ligand? Genetically modified mice and overexpression of genes encoding target receptors can provide evidence for a physiological or pathophysiological role; May lead to the development of a surrogate ligand for therapeutic use. 11. Recommendations for Formal Receptor Nomenclature (1) Recommendations based on 11 pairings for class A GPCRs; No recommendations for class B and class C orphan GPCRs 12. Recommendations for Formal Receptor Nomenclature (1) 13. Pairings reported by a single paper Pairings have been highlighted for: 30 class A orphan GPCRs 6 class B orphan GPCRs 1 class C orphan GPCR Minimum criterion is reproducibility; Majority are receptor overexpression linked to reporter system; potential for false positives; Further input is needed from the scientific community to validate these findings. 14. Pairings reported by a single paper 15. What are the remaining druggable orphan GPCRS? (1) No reported pairings (91 in total): 57 class A orphan GPCRs 28 class B orphan GPCRs 6 class C orphan GPCRs Remaining orphan GPCRs with knockout mouse phenotype reported = 22 No knockout mouse reported (yet?) = 62 Gene absent in mouse and rat = 7 Pseudogenes in human = 6 16. What are the remaining druggable orphan GPCRS? (2) These may include: Orphan receptors with activity in absence of an endogenous ligand; receptors may function without ligands by being constitutively active or by modulating the activity of other GPCRs, for example, by dimerization; Orphans activated by surrogate ligands; they may still represent a druggable target by the discovery of synthetic ligands; Orphans where a significant phenotype has been reported in genetically modified animals. 17. Conclusions The objective is to stimulate research into confirming pairings of orphan receptors where there is currently limited information and to identify cognate ligands for the remainingGPCRs; We need your expertise!!! www.guidetopharmacology.org Email: [email protected] org 18. The IUPHAR/BPS Guide to PHARMACOLOGY (since 2011) Increased target coverage to additionally include catalytic receptors, enzymes (including all kinases) and transporters; over 2600 targets in total; Detailed annotation for over 6800 small molecule and peptide ligands; www.guidetopharmacology.org; Please come to the NC-IUPHAR symposium tomorrow, Tues 15th, 15:30-17:00 to hear more! 19. Acknowledgements Tony Harmar Michael Spedding,Anthony Davenport, Steve Alexander andTom Bonner Members of NC-IUPHAR Joanna Sharman, Helen Benson, Elena Faccenda,Christopher Southan and Jamie Davies Amy E. Monaghan andWen Chiy Liew