title: Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.
abstract: The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic β-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477, USA. ecodd@its.jnj.com
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Codd
authors.forename: Judith
authors.initials: J
authors.lastname: Baker
authors.forename: Michael R
authors.initials: MR
authors.lastname: Brandt
authors.forename: Stewart
authors.initials: S
authors.lastname: Bryant
authors.forename: Chaozhong
authors.initials: C
authors.lastname: Cai
authors.forename: John R
authors.initials: JR
authors.lastname: Carson
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Chevalier
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Colburn
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Coogan
authors.forename: Scott L
authors.initials: SL
authors.lastname: Dax
authors.forename: Bart
authors.initials: B
authors.lastname: Decorte
authors.forename: Michael
authors.initials: M
authors.lastname: Kemmerer
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Legrand
authors.forename: James M
authors.initials: JM
authors.lastname: Lenhard
authors.forename: Angelique M
authors.initials: AM
authors.lastname: Leone
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: John R
authors.initials: JR
authors.lastname: Mabus
authors.forename: Mark E
authors.initials: ME
authors.lastname: McDonnell
authors.forename: Michael K
authors.initials: MK
authors.lastname: McMillian
authors.forename: James J
authors.initials: JJ
authors.lastname: McNally
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Stone
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Wang
authors.forename: Sui-Po
authors.initials: SP
authors.lastname: Zhang
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Flores
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D049108:Cell Enlargement / Q000187:drug effects; D045744:Cell Line, Tumor; D003533:Cyproheptadine / Q000031:analogs & derivatives / Q000633:toxicity*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D004285:Dogs; D004838:Epiphyses / Q000002:abnormalities / Q000378:metabolism; D005260:Female; D057166:High-Throughput Screening Assays; D006943:Hyperglycemia / Q000139:chemically induced* / Q000378:metabolism; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007340:Insulinoma / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists / Q000633:toxicity*; D010009:Osteochondrodysplasias / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000633:toxicity*; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D001786:Blood Glucose; D007328:Insulin; D009292:Narcotic Antagonists; D012702:Serotonin Antagonists; D003533:Cyproheptadine