title: RQ-00201894: A motilin receptor agonist causing long-lasting facilitation of human gastric cholinergically-mediated contractions.
abstract: The aim was to characterise RQ-00201894, a novel non-macrolide motilin agonist, using human recombinant receptors and then investigate its ability to facilitate cholinergic activity in human stomach. A reporter gene assay assessed motilin receptor function. Selectivity of action was determined using a panel of different receptors, ion channels, transporters and enzymes. Cholinergically-mediated muscle contractions were evoked by electrical field stimulation (EFS) of human gastric antrum. The results showed that RQ-00201894, motilin and erythromycin acted as full motilin receptor agonists (EC50: 0.20, 0.11, 69 nM, respectively). In this function, RQ-00201894 had >90-fold selectivity of action over its ability to activate the human ghrelin receptor (EC50 19 nM) and greater selectivity over all other receptors/mechanisms tested. In human stomach RQ-00201894 0.1-30 μM concentration-dependently increased EFS-evoked contractions (up to 1209%; pEC50 6.0). At 0.1-10 μM this activity was usually prolonged. At higher concentrations (3-30 μM) RQ-00201894 also caused a short-lasting muscle contraction, temporally disconnected from the increase in EFS-evoked contractions. RQ-00201894 10 μM did not consistently affect submaximal contractions evoked by carbachol. In conclusion, RQ-00201894 potently and selectively activates the motilin receptor and causes long-lasting facilitation of cholinergic activity in human stomach, an activity thought to correlate with an ability to increase gastric emptying.
authors.affiliation: Blizard Institute (National Centre for Bowel Research and Surgical Innovation), Barts and the London School of Medicine and Dentistry, 2 Newark Street, London, E1 2AT, UK.
authors.forename: John
authors.initials: J
authors.lastname: Broad
authors.affiliation: RaQualia Pharma Inc., Department of Pharmacology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: RaQualia Pharma Inc., Department of Pharmacology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Tajimi
authors.affiliation: RaQualia Pharma Inc., Department of Pharmacology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Sudo
authors.affiliation: Bariatric Surgery Department, Homerton University Hospital, Homerton Row, London, E9 6SR, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Góralczyk
authors.affiliation: Bariatric Surgery Department, Homerton University Hospital, Homerton Row, London, E9 6SR, UK.
authors.forename: Umesh
authors.initials: U
authors.lastname: Parampalli
authors.affiliation: Bariatric Surgery Department, Homerton University Hospital, Homerton Row, London, E9 6SR, UK.
authors.forename: Kesava
authors.initials: K
authors.lastname: Mannur
authors.affiliation: RaQualia Pharma Inc., Department of Pharmacology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Blizard Institute (National Centre for Bowel Research and Surgical Innovation), Barts and the London School of Medicine and Dentistry, 2 Newark Street, London, E1 2AT, UK. Electronic address: g.sanger@qmul.ac.uk.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Sanger
mesh_terms: D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004917:Erythromycin / Q000494:pharmacology; D005746:Gastric Emptying / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D054440:Receptors, Ghrelin / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000819:agonists*; D013270:Stomach / Q000187:drug effects*
chemical_list: D007211:Indoles; C000612843:RQ-00201894; D011964:Receptors, Gastrointestinal Hormone; D054440:Receptors, Ghrelin; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D004917:Erythromycin; D002217:Carbachol; D000109:Acetylcholine
keywords: Cholinergic activity; Gastroparesis; Human stomach; Motilin; RQ-00201894