Longlong Tu1, Zengbing Lu1, Man P Ngan1, Francis F Y Lam1, Claudio Giuliano2, Emanuela Lovati2, Claudio Pietra2, John A Rudd1,3. 1. School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong. 2. Research and Preclinical Development Department, Helsinn Healthcare SA, Lugano, Switzerland. 3. The Laboratory Animal Services Centre, The Chinese University of Hong Kong, Shatin, Hong Kong.
Abstract
BACKGROUND AND PURPOSE: HM01, a novel, orally bioavailable, brain-penetrating agonist of ghrelin receptors, ameliorates emesis in Suncus murinus. This study compared HM01's activity against motion sickness with that of the less brain-penetrating ghrelin receptor agonist, HM02. EXPERIMENTAL APPROACH: The potential of HM01 and HM02 to relax isolated mesenteric arteries and to increase feeding was investigated. Radio telemetry was used to record gastric slow waves and body temperature. Plethysmography was used to measure respiratory function. HM01 and HM02 were administered p.o. 1 hr prior to provocative motion, and c-Fos expression in brain sections was assessed. KEY RESULTS: HM01 and HM02 both relaxed precontracted arteries, yielding EC50 values of 2.5 ± 0.5 and 3.5 ± 0.4 nM respectively. HM01 increased feeding, but HM02 did not. Both compounds caused hypothermia and bradygastria. Motion induced 123 ± 24 emetic events. HM01, but not HM02, reduced motion-induced emesis by 67.6%. Motion increased c-Fos expression in the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMNV), medial vestibular nucleus (MVe), central nucleus of the amygdala, and paraventricular hypothalamic nucleus (PVH). HM01 alone increased c-Fos expression in the area postrema, NTS, DMNV, PVH, and arcuate hypothalamic nucleus; HM02 had a similar pattern except it did not increase c-Fos in the PVH. Both compounds antagonized the motion-induced increases in c-Fos expression in the MVe. CONCLUSIONS AND IMPLICATIONS: HM01 is more effective than HM02 in preventing motion-induced emesis. The difference in potency may relate to activation of ghrelin receptors in the PVH.
BACKGROUND AND PURPOSE: HM01, a novel, orally bioavailable, brain-penetrating agonist of ghrelin receptors, ameliorates emesis in Suncus murinus. This study compared HM01's activity against motion sickness with that of the less brain-penetrating ghrelin receptor agonist, HM02. EXPERIMENTAL APPROACH: The potential of HM01 and HM02 to relax isolated mesenteric arteries and to increase feeding was investigated. Radio telemetry was used to record gastric slow waves and body temperature. Plethysmography was used to measure respiratory function. HM01 and HM02 were administered p.o. 1 hr prior to provocative motion, and c-Fos expression in brain sections was assessed. KEY RESULTS: HM01 and HM02 both relaxed precontracted arteries, yielding EC50 values of 2.5 ± 0.5 and 3.5 ± 0.4 nM respectively. HM01 increased feeding, but HM02 did not. Both compounds caused hypothermia and bradygastria. Motion induced 123 ± 24 emetic events. HM01, but not HM02, reduced motion-induced emesis by 67.6%. Motion increased c-Fos expression in the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMNV), medial vestibular nucleus (MVe), central nucleus of the amygdala, and paraventricular hypothalamic nucleus (PVH). HM01 alone increased c-Fos expression in the area postrema, NTS, DMNV, PVH, and arcuate hypothalamic nucleus; HM02 had a similar pattern except it did not increase c-Fos in the PVH. Both compounds antagonized the motion-induced increases in c-Fos expression in the MVe. CONCLUSIONS AND IMPLICATIONS: HM01 is more effective than HM02 in preventing motion-induced emesis. The difference in potency may relate to activation of ghrelin receptors in the PVH.
Authors: Rishabh Verma; Farazul Hoda; Mawrah Arshad; Asif Iqubal; Ali Nasir Siddiqui; Mohammad Ahmed Khan; Syed Ehtaishamul Haque; Mohd Akhtar; Abul Kalam Najmi Journal: Med Cannabis Cannabinoids Date: 2021-05-21
Authors: Longlong Tu; Zengbing Lu; Man P Ngan; Francis F Y Lam; Claudio Giuliano; Emanuela Lovati; Claudio Pietra; John A Rudd Journal: Br J Pharmacol Date: 2020-02-03 Impact factor: 8.739
Authors: Longlong Tu; Julia Y H Liu; Zengbing Lu; Dexuan Cui; Man P Ngan; Peng Du; John A Rudd Journal: Front Pharmacol Date: 2021-12-03 Impact factor: 5.810
Authors: Gianfabio Giorgioni; Fabio Del Bello; Wilma Quaglia; Luca Botticelli; Carlo Cifani; E Micioni Di Bonaventura; M V Micioni Di Bonaventura; Alessandro Piergentili Journal: J Med Chem Date: 2022-02-14 Impact factor: 7.446
Authors: Mario Perelló; María P Cornejo; Pablo N De Francesco; Gimena Fernandez; Laurent Gautron; Lesly S Valdivia Journal: IBRO Neurosci Rep Date: 2022-03-12