Synthesis and biological evaluation of potent, selective, hexapeptide CCK-A agonist anorectic agents

Journal of Medicinal Chemistry
M E PiersonJ D Rosamond

Abstract

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.

References

Sep 1, 1991·Journal of Medicinal Chemistry·K ShiosakiA M Nadzan
Jan 1, 1986·Physiological Reviews·C A BaileM A Della-Fera
Jul 1, 1986·Journal of Medicinal Chemistry·R GuéganD Segondy
Sep 1, 1973·Journal of Comparative and Physiological Psychology·J GibbsG P Smith
Feb 1, 1981·The American Journal of Clinical Nutrition·H R KissileffG P Smith
Jan 1, 1994·Peptides·J N Crawley, R L Corwin
Mar 23, 1994·Annals of the New York Academy of Sciences·H E Raybould, K C Lloyd
Mar 23, 1994·Annals of the New York Academy of Sciences·G P Smith, J Gibbs
Mar 1, 1994·Pharmacology, Biochemistry, and Behavior·R D SimmonsJ R Rosamond

❮ Previous
Next ❯

Citations

Mar 8, 2011·Molecular Pharmaceutics·Oded OvadiaAmnon Hoffman
Nov 4, 2000·Expert Opinion on Investigational Drugs·P de TullioB Pirotte
Jul 1, 2010·Expert Opinion on Drug Discovery·Oded OvadiaHorst Kessler
Oct 26, 2005·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·T J LittleC Feinle-Bisset
Feb 4, 2010·Journal of Peptide Science : an Official Publication of the European Peptide Society·Hortensia RodríguezFernando Albericio
Nov 20, 2009·British Journal of Pharmacology·Erin E Cawston, Laurence J Miller
Feb 25, 2009·Expert Opinion on Therapeutic Targets·Ranjan Chakrabarti
Jul 10, 2019·Frontiers in Physiology·Donovan A ArguetaNicholas V DiPatrizio
Jul 6, 2000·Journal of Medicinal Chemistry·M E PiersonJ D Rosamond
Feb 2, 1999·Journal of Medicinal Chemistry·C P Kordik, A B Reitz

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.