α-Methyl tryptophanylphenylalanines and their arylethylamine “dipeptoid” analogues of the tetrapeptide cholecystokinin (30–33)

Abstract A series of N -alkyl carbamate blocked α-Me-Trp-Phe and α-Me-Trp-phenethylamides has been identified as “dipeptoid” analogues of CCK - 4 (CCK 30–33). These compounds have micromolar affinity for the type-B central CCK receptor, some of which increase the firing rate of CCK-B rich neurons in isolated slices containing the ventro-medial nucleus (VMN) of the hypothalamus from rat brain. SAR studies indicate that the preferred N -substituents are bulky groups such as Boc-, Amoc-, Adoc and TcBoc-, and that d -α-Me-Trp and l -Phe configurations are preferred. The C -terminal phenyl group can be replaced by substituted phenyl and selected heteroaryl groups such as 2-thienyl and 2-pyridyl. The C -terminal amide group can be replaced by -CH 2 OH, -CO-piperidide, and even -H without loss of binding affinity e.g. Boc- dl -α-Me-Trp-CH 2 CH 2 Ph as K i of 11 μM. These small non-peptide molecules have comparable receptor affinities to certain full tetrapeptide analogues of CCK -4 and compound 24 , TcBoc- dl -α-McTrp-phenylethylamide, is the first CCK - dipeptoid with CCK - B like agonist properties so far described.