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