Preclinical toxicity studies of an adenosine agonist, N-(2,2-diphenylethyl) adenosine.
N-(2,2-Diphenylethyl)adenosine (DPEA) has been identified as a potential antipsychotic agent acting via stimulation of adenosine receptors. The projected human therapeutic dose, based on animal studies, is 2-3 mg/kg. DPEA has been tested for potential toxicity in mice, rats, dogs and monkeys. Following single oral doses, median lethal dose values were approximately 10-fold greater in rats than in mice, although similar clinical signs including reduced activity, prostration, and necrosis of the tail were seen in both species. DPEA was well tolerated at daily doses up to 40 mg/kg in rats for 2 weeks. A no observed effect level (NOEL) was not identified in the dog or monkey studies. Reduced activity, dacryorrhea, ptosis, hypothermia, necrosis of the tail, and death occurred in rats given 120 and 160 mg/kg. Pathologic changes consisted of pancreatitis, gastric erosion/ulceration, lymphocyte depletion of the thymus, and pulmonary congestion and hemorrhage at 80 mg/kg or greater. In dogs, sporadic emesis was noted at 12.5 mg/kg and greater, and significant pathologic changes consisted of coronary arteritis associated with myocardial lesions and lymphocyte depletion at 25 and 50 mg/kg, pancreatic acinar necrosis at 50 mg/kg, and renal tubular degeneration at 12.5 mg/kg and greater. Emesis and depression were noted at 25 and 50 mg/kg in monkeys. Renal tubular dilatation and degeneration at 25 and 50 mg/kg were noted in the monkeys. These studies demonstrated that DPEA produced a range of adverse effects in common laboratory animal species.
Macallum
G E
GE
Parke-Davis Research Institute, Division of Warner-Lambert Canada Inc., Mississauga, Ontario, Canada.
Walker
R M
RM
Barsoum
N J
NJ
Smith
G S
GS
D000241:Adenosine / Q000031:analogs & derivatives* / Q000502:physiology* / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains
C053810:N(6)-(2,2-diphenylethyl)adenosine; D000241:Adenosine