title: Effects of R-102444 and its active metabolite R-96544, selective 5-HT2A receptor antagonists, on experimental acute and chronic pancreatitis: Additional evidence for possible involvement of 5-HT2A receptors in the development of experimental pancreatitis.
abstract: The effects of R-102444 ((2R, 4R)-4-lauroyloxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride) and its active metabolite R-96544 ((2R, 4R)-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-4-hydroxy-1-methylpyrrolidine hydrochloride), potent and selective 5-hydroxytryptamine 2A (5-HT2A) receptor antagonists, on development of pancreatitis were investigated in experimental models of acute and chronic pancreatitis. Rat acute pancreatitis was induced by caerulein (20 microg/kg) intraperitoneal injection and by pancreatic duct ligation. In both the models, serum amylase and lipase activities were markedly increased. R-102444 dose-dependently reduced these enzyme activities at a dose range of 10 to 100 mg/kg (p.o.) for the caerulein model and 0.3 to 10 mg/kg (p.o.) for the ligation model. In a mouse model of acute pancreatitis induced by a choline-deficient, ethionine (0.5%)-supplemented diet, subcutaneous administration of R-96544 (10-100 mg/kg, bid) reduced serum amylase activity. Histological analysis showed that R-96544 dose-dependently attenuated pancreatic necrosis, inflammation and vacuolization. The effect of R-102444 was further examined in male Wistar Bonn/Kobori rats (4-9 months of age) which spontaneously show pancreatic fibrosis and parenchymal destruction compatible with human chronic pancreatitis. In Wistar Bonn/Kobori rats (from 3 to 9 months of age) fed a diet containing 0.017% and 0.17% of R-102444, pancreatic weight, pancreatic protein and amylase content were higher compared to those in non-treated pancreatitis control rats. Histological analysis showed that R-102444 suppressed parenchymal destruction and replacement with adipose tissue, indicating inhibition of pancreatic atrophy. These results clearly indicate that R-102444 and R-96544 inhibit the progression of acute and chronic pancreatitis and support the contention of possible involvement of 5-HT2A receptors in the progression of experimental pancreatitis.
authors.affiliation: Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Tokyo 140-8710, Japan. togawa@sankyo.co.jp
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Ogawa
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Fukushige
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Tani
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Asai
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood / Q000378:metabolism; D000818:Animals; D002108:Ceruletide / Q000008:administration & dosage / Q000633:toxicity; D002794:Choline / Q000008:administration & dosage; D002908:Chronic Disease; D019587:Dietary Supplements; D005001:Ethionine / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D008026:Ligation / Q000009:adverse effects; D008049:Lipase / Q000097:blood / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010183:Pancreatic Ducts / Q000601:surgery; D010195:Pancreatitis / Q000209:etiology / Q000517:prevention & control*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C476157:(2R,4R)-4-hydroxy-2-(2-(2-(2-(3-methoxy)phenyl)ethyl)phenoxy)ethyl-1-methylpyrrolidine hydrochloride; D011759:Pyrrolidines; C421542:R-102444; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D002108:Ceruletide; D008049:Lipase; D000681:Amylases; D002794:Choline; D005001:Ethionine