ALPHA-METHYL TRYPTOPHANYLPHENYLALANINES AND THEIR ARYLETHYLAMINE DIPEPTOID ANALOGS OF THE TETRAPEPTIDE CHOLECYSTOKININ (30-33)

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 -CH2OH, -CO-piperidide, and even -H without loss of binding affinity e.g. Boc-dl-α-Me-Trp-CH2CH2Ph as Ki 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. © 1990.