title: Partial agonist activity of R3(BΔ23-27)R/I5 at RXFP3--investigation of in vivo and in vitro pharmacology.
abstract: Relaxin family peptide receptor 3 (RXFP3) is a G-protein coupled receptor mainly expressed in the brain and involved in appetite regulation. Previous studies in lean Wistar rats during the light phase have shown that the chimeric peptide R3(BΔ23-27)R/I5 suppresses food intake stimulated by an RXFP3 agonist, but has no effect on food intake when administered alone. We wanted to further investigate if R3(BΔ23-27)R/I5 on its own is able to antagonize the basal tone of the relaxin-3/RXFP3 system and therefore characterized the pharmacology of R3(BΔ23-27)R/I5 in vivo and in vitro. R3(BΔ23-27)R/I5 was intracerebroventricularly (ICV) injected in diet induced obese (DIO) Wistar rats and food intake was automatically measured during the dark phase when feeding drive is high. In our hands, R3(BΔ23-27)R/I5 alone did not have a significant effect on food intake during 24h following administration. Consistent with previous results, relaxin-3 stimulated food intake in satiated lean rats. R3(BΔ23-27)R/I5 was characterized in vitro using [(35)S]-GTPγS binding and cAMP assays, both assessing Gαi-protein mediated signalling, and dynamic mass redistribution (DMR) assays capturing the integrated cell response. R3(BΔ23-27)R/I5 showed partial agonist activity in all three functional assays. Thus, since R3(BΔ23-27)R/I5 displays partial RXFP3 agonist properties in vitro, further in vivo studies including additional tool compounds are needed to address if antagonizing relaxin-3/RXFP3 basal tone is a therapeutically relevant mechanism to regulate food intake and body weight.
authors.affiliation: Discovery Sciences, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Kristensson
authors.affiliation: Respiratory, Inflammatory and Autoimmune iMED, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden; Cardiovascular and Metabolic Diseases iMED, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden.
authors.forename: Gaëll
authors.initials: G
authors.lastname: Mayer
authors.affiliation: Cardiovascular and Metabolic Diseases iMED, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden; DSM Laboratory Animal Science, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Ploj
authors.affiliation: Cardiovascular and Metabolic Diseases iMED, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Wetterlund
authors.affiliation: Respiratory, Inflammatory and Autoimmune iMED, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Arlbrandt
authors.affiliation: Cardiovascular and Metabolic Diseases iMED, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Björquist
authors.affiliation: Respiratory, Inflammatory and Autoimmune iMED, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden.
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Wissing
authors.affiliation: Discovery Sciences, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Castaldo
authors.affiliation: Discovery Sciences, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden. Electronic address: niklas.hp.larsson@astrazeneca.com.
authors.forename: Niklas
authors.initials: N
authors.lastname: Larsson
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D059305:Diet, High-Fat / Q000009:adverse effects; D004328:Drive; D004435:Eating / Q000187:drug effects / Q000523:psychology; D008297:Male; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology / Q000523:psychology; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D018000:Receptors, Peptide / Q000819:agonists*; D011994:Recombinant Proteins / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019440:Anti-Obesity Agents; D010455:Peptides; C577472:RXFP3 protein, rat; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D011994:Recombinant Proteins
keywords: GPCR; Partial agonism; R3(BΔ23–27)R/I5; RXFP3; Relaxin family peptide receptor 3; Relaxin-3