FPL 14294: a novel CCK-8 agonist with potent intranasal anorectic activity in the rat.
Cholecystokinin octapeptide (CCK-8) induces satiety in many species including man. However, its therapeutic utility is restricted due to its short biological half-life and poor bioavailability. FPL 14294 [4-(sulfoxy)-phenylacetyl(MePhe6)CCK-6] is a CCK analog with enhanced metabolic stability that was comparable to CCK-8 in potency to contract isolated gallbladder and in affinity at the CCK-A and CCK-B receptor. However, FPL 14294 was more than 200 times more potent than CCK-8 in inhibiting 3-h feeding in 21-h fasted rats. FPL 14294 also possessed intranasal anorectic activity at 5 micrograms/kg, while CCK-8 was inactive at doses up to 500 micrograms/kg. Anorectic activity was inhibited by pretreatment with a CCK-A antagonist (MK-329) but not by a CCK-B antagonist (L365,260). The anorectic effects of CCK-8 and FPL 14294 were the result of a direct effect on feeding and not caused indirectly by effects on water intake. These results indicate that FPL 14294 is a potent, intranasally active, anorectic agent whose enhanced in vivo potency over that of CCK-8 may reflect differences in stability, bioavailability, or receptor kinetics.
Simmons
R D
RD
Biochemistry Department, Pharmaceuticals, Rochester, NY 14603.
Blosser
J C
JC
Rosamond
J R
JR
D000281:Administration, Intranasal; D000595:Amino Acid Sequence; D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D004285:Dogs; D004326:Drinking / Q000187:drug effects; D005704:Gallbladder / Q000187:drug effects; D006168:Guinea Pigs; D006207:Half-Life; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D012844:Sincalide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000502:physiology*
D001067:Appetite Depressants; D011949:Receptors, Cholecystokinin; C087645:FPL 14294; D012844:Sincalide