A peptide agonist of the guanylate cyclase C receptor
Linaclotide is a peptide agonist of the guanylate cyclase C receptor (Ki = 16.4 nM in a radioligand binding assay using mouse intestinal mucosa).1 Luminal exposure to 5 μg of linaclotide stimulates fluid secretion and cGMP concentration in jejunal loops isolated from wild-type mice but not guanylate cyclase C receptor-null mice. Linaclotide (100 μg/kg) increases intestinal transit rate in wild-type mice. It also reduces the number of phosphorylated ERK-positive dorsal horn neurons in the thoracolumbar spinal cord, a marker of nociceptive signaling, following noxious colorectal distension and mechanical hypersensitivity in a mouse model of TNBS-induced colitis.2 Formulations containing linaclotide have been used for the treatment of constipation and pain associated with irritable bowel syndrome.
1.Bryant, A.P., Busby, R.W., Bartolini, W.P., et al.Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tractLife Sci.86(19-20)760-765(2010) 2.Castro, J., Harrington, A.M., Hughes, P.A., et al.Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphateGastroenterology145(6)1334-1346(2013)
|
Animal experiment: |
Mice: To determine oral bioavailability, three groups (n=3) of female CD-1 mice receive linaclotide (8 mg/kg) intravenously (i.v.), while two groups (n=3) receive linaclotide (8 mg/kg) by gavage (p.o.). Blood is allowed to clot for 5 min, centrifuged at 13,000×g for 3 min, and the serum is collected and stored at ?80 °C until sample preparation and analysis by LC-MS/MS[1]. |
|
参考文献: [1]. Bryant AP, et al. Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci. 2010 May 8;86(19-20):760-5. |
|
动态评分
0.0