Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.
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.
Codd
Ellen E
EE
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477, USA. ecodd@its.jnj.com
Baker
Judith
J
Brandt
Michael R
MR
Bryant
Stewart
S
Cai
Chaozhong
C
Carson
John R
JR
Chevalier
Kristen M
KM
Colburn
Raymond W
RW
Coogan
Timothy P
TP
Dax
Scott L
SL
Decorte
Bart
B
Kemmerer
Michael
M
Legrand
Edmund K
EK
Lenhard
James M
JM
Leone
Angelique M
AM
Lin
Ling
L
Mabus
John R
JR
McDonnell
Mark E
ME
McMillian
Michael K
MK
McNally
James J
JJ
Stone
Dennis J
DJ
Wang
Charles Y
CY
Zhang
Sui-Po
SP
Flores
Christopher M
CM
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
D001786:Blood Glucose; D007328:Insulin; D009292:Narcotic Antagonists; D012702:Serotonin Antagonists; D003533:Cyproheptadine