Antifertility activity and general pharmacological properties of ORF 13811: a synthetic analog of zoapatanol.
ORF 13811, a synthetic analog of zoapatanol, was evaluated in a variety of in vivo and in vitro biological test systems to determine antifertility and uterotonic activity as well as its general pharmacological profile. ORF 13811 is a potent antifertility agent after oral administration in a number of animal species including mice, rats, guinea pigs, dogs and baboons. The single oral ED50 for contragestational activity in the pregnant guinea pig (day 22), mouse (day 16) and rat (day 16) is in the range of 6 to 10 mg/kg. In pregnant beagle dogs, a dose-related contragestational effect was obtained within several days after oral administration of ORF 13811 in the dosage range of 10 to 30 mg/kg. ORF 13811, when administered to pregnant baboons, caused dose-related vaginal bleeding and evacuation of uterine contents within 3 days following treatment with oral doses of 40 to 60 mg/kg. Serum progesterone levels were decreased in baboons and the degree of reduction correlated with contragestational activity. ORF 13811 was also effective in inhibiting implantation in mice, rats and hamsters, but required higher dose levels than those of the post-implantive treatments. In vitro uterotonic properties of ORF 13811 were demonstrated by its ability to induce contraction of uterine strips obtained from female guinea pigs at two different reproductive stages (day 15 of the estrous cycle and day 22 of pregnancy). In these preparations ORF 13811 was approximately 1/30 to 1/50th as potent as PGF2 alpha. In a series of pharmacological tests, ORF 13811 was found to possess slight sedative properties but was devoid of activity on pulmonary, gastrointestinal, and immune systems as well as in a number of biochemical tests, data not reported here. However, in cardiovascular studies, ORF 13811 appears to possess a vasoconstrictor profile in the dog, monkey and baboon as indicated by an increase in mean arterial blood pressure as well as total peripheral and regional vascular resistances. The in vitro pharmacological profile of ORF 13811 was examined in myocardial tissue and vascular smooth muscle test systems and compared to PGF2 alpha. ORF 13811 was found to contract rat aortic strips, 15 times less potent than PGF2 alpha. The compound had no direct effect on isolated guinea pig atria or papillary muscle. In summary, ORF 13811 is a potent orally active antifertility agent characterized primarily as a contractor of uterine and vascular smooth muscle.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003271:Contraceptive Agents, Female / Q000633:toxicity*; D004224:Diterpenes / Q000633:toxicity*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D000882:Haplorhini; D051379:Mice; D035924:Montanoa; D010082:Oxepins / Q000633:toxicity*; D010215:Papio; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D003271:Contraceptive Agents, Female; D004224:Diterpenes; D010082:Oxepins; C442248:zoapatanol; C043087:ORF 13811