Novel and potent gastrin and brain cholecystokinin antagonists from Streptomyces olivaceus. Taxonomy, fermentation, isolation, chemical conversions, and physico-chemical and biochemical properties.
The discovery and physico-chemical characterization of three novel and minor virginiamycin M1 analogs as potent gastrin antagonists from a culture of a strain of Streptomyces olivaceus are described. These analogs are L-156,586, L-156,587 and L-156,588. They are, respectively, 15-dihydro-13,14-anhydro-, 13,14-anhydro- and 13-desoxy-analogs of virginiamycin M1. We also chemically converted virginiamycin M1 (via L-156,587) to L-156,586 and its unnatural epimer, L-156,906. These analogs are competitive and selective antagonists of gastrin and brain cholecystokinin binding at nanomolar concentrations. These are the most potent gastrin/brain cholecystokinin antagonists from natural products. The same compounds showed poor Gram-positive antibiotic activity versus virginiamycin M1. Structurally related Gram-positive antibiotics, griseoviridin and madumycin I, were inactive in gastrin and brain cholecystokinin binding at up to 100 microM.
Lam
Y K
YK
Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
Bogen
D
D
Chang
R S
RS
Faust
K A
KA
Hensens
O D
OD
Zink
D L
DL
Schwartz
C D
CD
Zitano
L
L
Garrity
G M
GM
Gagliardi
M M
MM
D000818:Animals; D001419:Bacteria / Q000187:drug effects; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D005285:Fermentation; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D013302:Streptomyces / Q000145:classification / Q000378:metabolism*; D014769:Virginiamycin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D005755:Gastrins; D011949:Receptors, Cholecystokinin; D014769:Virginiamycin; C069915:15-dihydro-13,14-anhydrovirginiamycin M1; C069917:13-deoxyvirginiamycin M1; C069916:13,14-anhydrovirginiamycin M1; D002766:Cholecystokinin