Synthesis and biological evaluation of potent, selective, hexapeptide CCK-A agonist anorectic agents.
Cholecystokinin (CCK) is a 33-amino acid peptide with multiple functions in both the central nervous system (via CCK-B receptors) and the periphery (via CCK-A receptors). CCK mediation of satiety via the A-receptor subtype suggest a role for CCK in the management of obesity. The carboxy terminal octapeptide (CCK-8) is fully active in this regard, but is lacking in receptor selectivity, metabolic stability, and oral bioavailability. Inversion of the chirality of Asp7 in conjunction with N-methylation of Phe8 produces compound 5 which exhibits high affinity and 2100-fold selectivity for CCK-A receptors. Compound 6 (Hpa(SO3H)-Nle-Gly-Trp-Nle-MeAsp-Phe-NH2), derived from moving the N-methyl group from Phe to Asp, decreased CCK-B affinity substantially without affecting CCK-A affinity, giving a compound with 6600-fold selectivity for CCK-A receptors. These compounds inhibit food intake with nanomolar potency following intraperitoneal administration in fasted rats. In addition to greater potency, compound 6 produces weight loss in rats when administered over nine consecutive days. Intranasal administration of 6 potently inhibits feeding in beagle dogs. Compound 6 produces potent anorectic activity via the CCK-A receptor system.
Pierson
M E
ME
Astra Arcus USA, Rochester, New York 14602, USA.
Comstock
J M
JM
Simmons
R D
RD
Kaiser
F
F
Julien
R
R
Zongrone
J
J
Rosamond
J D
JD
D000281:Administration, Intranasal; D000596:Amino Acids / Q000032:analysis; D000818:Animals; D001067:Appetite Depressants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D004285:Dogs; D004435:Eating / Q000187:drug effects; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists* / Q000378:metabolism
D000596:Amino Acids; D001067:Appetite Depressants; D009842:Oligopeptides; D010455:Peptides; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; C110194:hexapeptide CCK-A