Structure-Activity Relationships in the Cyproheptadine Series

El, Engelhardt; Hc, Zell; Ws, Saari; Me, Christy; Cd, Colton; Ca, Stone; Jm, Stavorski; Hc, Wenger; Ct, Ludden

doi:10.1021/jm00330a022

Cited by 56 publications

(26 citation statements)

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“…The known pharmacologic actions of CPH are apparently not involved in either its pancreotoxicity or its ability to inhibit insulin secretion. This reasoning arises from the fact that DMCPH is pancreotoxic (12) and inhibits insulin release as shown in this study but does not possess the antiserotonin or antihistaminic action of CPH (4).…”

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confidence: 84%

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Cyproheptadine and Beta Cell Function in the Rat: Insulin Secretion from Pancreas Segments in vitro

Rickert

Fischer

1975

Experimental Biology and Medicine

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Cyproheptadine (CPH) causes alterations of structure and function in the rat pancreas (1, 2). Daily oral doses of CPH produce pancreatic @-cell vacuolization, altered glucose tolerance and nonfasting hyperglycemia. These abnormalities suggested that ,&cells in CPH-treated rats may not be capable of normal insulin release. To investigate this possibility, glucose-stimulated and basal insulin release from pancreas segments obtained from CPH-treated rats were determined in vitro. Several stimulators of insulin release, which may act through different mechanisms, were employed to determine whether the CPH-damaged ,&cell was generally refractory to such stimuli.Both CPH and a metabolite desmethyl-CPH (DMCPH) are present in rat pancreatic tissue after a pancreotoxic dose of CPH (3). To examine whether the presence of these substances in the pancreas could alter insulin release, CPH and DMCPH were tested for their ability to modify glucosestimulated insulin release from segments of pancreas taken from untreated rats.The results of these studies help to explain the glucose intolerance which occurs in rats after administration of CPH and suggest that inhibition of insulin secretion due to tlzatment with this drug may be caused by more than one mechanism.Materials and Methods. Male, Wistar rats (Simonsen Laboratories, Gilroy, Ca.) weighing 230-280 g were used. The animals had free access to food (Wayne Lab Blox, Allied Mills, Chicago, Ill.) and water, and were housed in suspended, stainless steel cages under controlled lighting (lights off, 1900-0600 hr).

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confidence: 84%

“…Cyproheptadine (4-(5H-dibenzo[a, dlcyclohepten-5-ylidine)-l -met h y 1 piper i d in e) (CPH) was supplied as the hydrochloride monohydrate by the Merck Institute for Therapeutic Research, West Point, Pa. Desmethyl-CPH (DMCPH) was synthesized by the method of Engelhardt et al (4).…”

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confidence: 99%

Cyproheptadine and Beta Cell Function in the Rat: Insulin Secretion from Pancreas Segments in vitro

Rickert

Fischer

1975

Experimental Biology and Medicine

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“…4-(5-dibenzo[a,d]cycloheptatrienylidene)-piperidine (DMCPH) was syn thesized using the method of Engelhardt et al [15]. Cyproheptadine-10,11 -epoxide (CPH-epoxide) and desmethylcyproheptadine-10,11 -epoxide (DMCPHepoxide) were isolated and purified from rat urine as described by Chow and Fischer [14], All chemicals were greater than 99 % pure, as determined by thinlayer chromatography and high-performance liquid chromatography (HPLC) [14].…”

Section: Methodsmentioning

confidence: 99%

“…Fifty-dayold animals were used for comparison because forma tion of cytoplasmic vacuoles has been shown pre viously in B cells of adult rats (including 50-day-old rats) following the same dosage regimen [3], The ani mals were killed 24 h after the last dose. Pancreatic tissue was obtained for insulin and glucagon determi nation and electron microscopy [15], Glucagon was measured because previous results from adult animals indicated that the effects of CPH were specific for insu…”

Section: Effects Of Cph In the Pancreas Of Rats At Various Agesmentioning

confidence: 99%

Postnatal Changes in the Insulin-Depleting Action and Disposition of Cyproheptadine in Rats

Chow¹,

Fischer²

1991

Dev Pharmacol Ther

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The relationship between age-related differences in cyproheptadine (CPH)- induced alteration of endocrine pancreas function and the disposition of the drug was examined in this study. Various doses of CPH (5, 11, 22.5 or 45 mg/kg) were given orally once daily for 2 days to 10-, 15-, 25- and 50-day-old rats. Pancreatic and serum insulin measured 24 h after the second dose showed a drug-dependent decline, and the extent of this effect was dependent on the dose administered and the age of the animal. In 50-day-old rats, a significant reduction in pancreatic and serum insulin was detected only after high doses (22.5 and 45 mg/kg) of the drug. However, in 10- and 15-day-old rats, the effects were observed after the lowest dose (5 mg/kg). In separate experiments, the concentrations of CPH and its active metabolites, desmethylcyproheptadine (DMCPH), desmethylcyproheptadine-10,11-epoxide (DMCPH-epoxide) and cyproheptadine-10,11-epoxide (CPH-epoxide), were measured in the pancreas, liver and lung of neonatal and young rats at various times after the second dose of CPH (11 mg/kg). In the younger age groups (10- and 15-day-olds), there were significantly higher tissue levels of unchanged drug at all times examined. Certain of the drug metabolites known to be inhibitors of insulin synthesis had higher and/or more prolonged tissue concentrations in younger animals. For example, the metabolite CPH-epoxide was found only in tissues from younger age groups. Twenty-four hours after the second dose of CPH, no drugderived product was present in tissues of 25- and 50-day-old rats, whereas significant amounts of DMCPH-epoxide, a potent CPH metabolite inhibiting insulin synthesis, was detected in the tissues of 10- and 15-day-old rats. The data show that there are age-related differences in the susceptibility of pancreatic B cells to the actions of CPH, and that these differences are associated with age-related changes in the disposition of the drug.

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“…17 Merck introduced a cyclic analogue of pheniramine known as cyproheptadine. 18 It had similar properties to chlorpheniramine, but was also of some value in the prophylaxis of migraine due to its ability to act as a 5-HT 2 antagonist. It is now reserved for refractory cases of migraine.…”

Section: Monoaminopropyl Antihistaminesmentioning

confidence: 99%

Drugs Originating from the Screening of Organic Chemicals

Sneader

2005

Drug Discovery

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Structure-Activity Relationships in the Cyproheptadine Series

Cited by 56 publications

References 0 publications

Cyproheptadine and Beta Cell Function in the Rat: Insulin Secretion from Pancreas Segments in vitro

Cyproheptadine and Beta Cell Function in the Rat: Insulin Secretion from Pancreas Segments in vitro

Postnatal Changes in the Insulin-Depleting Action and Disposition of Cyproheptadine in Rats

Drugs Originating from the Screening of Organic Chemicals

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