WIN 64821, A NEW COMPETITIVE ANTAGONIST TO SUBSTANCE-P, ISOLATED FROM AN ASPERGILLUS SPECIES - STRUCTURE DETERMINATION AND SOLUTION CONFORMATION

Two new diketopiperazine dimers, WIN 64821 (1a) and WIN 64745 (2), were isolated from an Aspergillus culture originally isolated from soil and their structures established on the basis of chemical and spectroscopic evidence. The dimer 1a has C1 symmetry with each of two equivalent monomeric subunits biosynthetically constructed from one phenylalanine and one tryptophan residue. Dimer 1a is a competitive antagonist to substance P (SP) at the human NK1 receptor with an inhibitor affinity constant (K(i)) of 230 +/- 30 nM against [I-125]SP in human astrocytoma cells. The solution structures of la and the nonsymmetrical methylation derivative 1b were determined by analysis of NMR data and molecular modeling. The solution structures, together with some structure-activity data, suggest a probable binding conformation for these molecules at the NK1 receptor.