The ghrelin receptor agonist, HM01, activates the innervation of the colon to initiate coordinated propulsive contractions and bowel emptying

      Agonists of the defined ghrelin receptor, GHSR1a, that cross the blood-central nervous system barrier, stimulate defecation. It has been suggested that some ghrelin receptor agonists, such as relamorelin, have direct effects on the colon. In this study we have investigated effects of a newly developed small molecule ghrelin agonist, HM01. HM01 increased intracellular Ca2+ with an EC50 of 1 nM in GHSR1a transfected HEK293 cells. The GHSR1a antagonist, YIL781, caused a rightward shift in the concentration response curve, pA2: 7.34. Intravenous HM01 increased amplitudes and frequencies of phasic pressure increases in the colorectum; threshold for effect 0.01-0.03 mg/kg. 0.03-0.1 mg/kg caused expulsion of colonic contents. Maximal effect was at 1 mg/kg. Stimulation of colorectal propulsion was prevented if the pelvic ganglia were bilaterally removed or by intravenous YIL781 (3 mg/kg). A second sub-maximal dose of HM01 (0.1 mg/kg), given 2 hr after the first dose, was about 50% effective compared to the first. Compared to capromorelin, which has been tested as a treatment for the constipation of spinal cord injury (Ellis et al 2015), HM01 had a similar potency in transfected cells, but was about 10 fold more potent in vivo, suggesting that it more effectively accesses GHSR1a in the spinal defecation centres. Thus HM01 is a potential therapeutic for the treatment of constipation. A similar effect of HM01 in stimulating defecation was shown in animal model of Parkinson’s disease (Karasawa 2014).
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