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

Two new diketopiperazine dimers, WIN 64821 (1a) and WIN 64745 (2), wer e isolated from an Aspergillus culture originally isolated from soil a nd their structures established on the basis of chemical and spectrosc opic evidence. The dimer 1a has C1 symmetry with each of two equivalen t monomeric subunits biosynthetically constructed from one phenylalani ne 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 astrocyto ma cells. The solution structures of la and the nonsymmetrical methyla tion derivative 1b were determined by analysis of NMR data and molecul ar modeling. The solution structures, together with some structure-act ivity data, suggest a probable binding conformation for these molecule s at the NK1 receptor.