In memory of…
Anthony (Tony) John Harmar, FRSE28 November 1951 – 10 April 2014
Orphan GPCRs: an update Adam J. Pawson Monday 14th July 2014, WCP2014
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.
Updating the GPCR list
• 2005
• 2013
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);
Orphan receptors
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;
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;
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;
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.
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
Recommendations for Formal Receptor Nomenclature (1)
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.
Pairings reported by a single paper
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
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.
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 remaining GPCRs;
• We need your expertise!!!• www.guidetopharmacology.org• Email:
curators@guidetopharmacology org
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!
Acknowledgements
• Tony Harmar• Michael Spedding, Anthony
Davenport, Steve Alexander and Tom Bonner
• Members of NC-IUPHAR• Joanna Sharman, Helen Benson,
Elena Faccenda, Christopher Southan and Jamie Davies
• Amy E. Monaghan and Wen Chiy Liew
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