Radioligand-Binding and Molecular-Imaging Techniques for the Quantitative Analysis of Established and Emerging Orphan Receptor Systems

互联网2014-02-14

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Radioligand binding is widely used to characterize receptors and to determine their anatomical distribution, particularly the superfamily of rhodopsinlike, seven-transmembrane-spanning G protein-coupled receptors (GPCRs). More than 200 receptors that transduce many important physiological processes and are the target for about 50% of all drugs have been identified in this family (1 –6 ) . A further approx 160 or so ″orphan″ GPCRs have been predicted to exist from the human genome and have mRNA sequences characteristic of 7TM GPCRs, but their endogenous ligands await identification. Most of these receptors have been artificially expressed in cell lines linked to a reporter sys- tem to identify when a ligand binds to the receptor (see Chapter 2 ). This ″re- verse pharmacology″ approach continues to be used to screen compounds from existing or new combinatorial libraries of biologically active molecules, and has been very successful. More than 45 receptors have been ″de-orphanized″ or paired with their cognate ligand, with nearly half of these putative endo- genous transmitters turning out to be peptides (see Table 1 ). The number of pairings continues to increase. It is estimated that about 70 of the remaining orphan receptors could turn out to have a peptidic ligand (3 ).

Table 1 Orphan Receptors Recently Paired With Their Cognate Peptidic Ligands

Year	Human peptide	Orphan receptor	Ligand source
1995	Nociceptin/Orphanin FQ	ORL-1/OFQ	Porcine brain
1998	Apelin	Apelin/APJ	Bovine stomach
	Orexin A and B (hypercretin 1+2)	Orexin 1 and 2	Rat brain
	Prolactin Releasing Peptide (PRrP)	hGRP-3/GPR10	Bovine hypothalamus
1999	Ghrelin (motilin related peptide)	Ghrelin/GHS-R	Rat stomach
	Melanin concentrating hormone (MCH)	MCHR₁	Rat whole brain
	Motilin	GPR38	Peptide library
	Tuberoinfundibular peptide 39 (TIP39)	PTH₂ R	Bovine hypothalamus
	Urotensin-II	UT/GPR14/SENR	Peptide library
2000	Neuromedin U-25 (NMU25)	FM3 and FM4	Peptide library
	Neuropeptides FF and AF	NPFF-R1	Bovine brain
2001	Metastin (Kisspeptin-54)	GPR54	Human placenta
	MCH	MCHR₂	Peptide library
	Urocortin II and I (stresscopins)	CRF₂	Peptide library
2002	Relaxin	LGR7 and LGR8	Peptide library
	Bovine adrenomedullary peptide 22 (BAM-22)	SNSR3 and SNSR4	Peptide library
	Neuropeptides B and W	GPR7 and GPR8	Peptide library
2003	QRFP43 (P52)	SP9155/GPR103	Genome database
	Relaxin-3/INSL7	GPR135/SALPR	Porcine brain
See refs. 2 and 3 for further information and citations to original papers.

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