Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK1 receptor antagonist

This paper describes the synthesis and physical and biological effects of i ntroducing different substituents at the a-position of the tryptophan conta ining neurokinin-l receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-(( S)-1-phenyl-ethylcarb amoyl)- ethyl] -carbamic acid benzofuran-2-ylmethyl e ster (CI 1021). The described compounds all exhibit less than 5 nM binding affinities for the human neurokinin-l receptor and selectivity over the tac hykinin NK2 and NK3 receptor subtypes. Application of variable temperature nuclear magnetic resonance spectroscopy studies of the amide and urethane p rotons was utilized to determine the existence of an intramolecular hydroge n bond. This intramolecular hydrogen bond increases the apparent lipophilic ity to allow increased central nervous system penetration and pharmacologic al activity (gerbil foot tap test) in the case of the highest affinity comp ound [(S)-1-dimethylaminomethyl2-(1H-indol-3-yl)- 1-((S)-1-phenyl-ethylcarb amoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (PD 174424) over th ose analogues that could not form an intramolecular hydrogen bond.