ABSORPTION, EMISSION, AND CHIROPTICAL SPECTRA OF NEUROKININ-1 TACHYKININ RECEPTOR ANTAGONISTS - THE ROLE OF CHARGE-TRANSFER STATES ON THE BIOLOGICAL-ACTIVITY

A spectroscopic investigation, based on both electronic absorption and emission spectra as well as on chiroptical data, was performed, on no vel neurokinin 1 (NK1) tachykinin receptor antagonists, exhibiting int eresting biological activity. These pseudopeptides have two fluorophor es, i.e., indole (I) and naphthalene (N), and a central scaffold with different conformational mobility. Absorption spectra in methanol show the presence of a new band with respect to the sum spectrum of the is olated chromophores at around 285 nm, the intensity of which linearly increases as the bioactivity increases. This absorption disappears by using dioxane as solvent. It is ascribed to an intramolecular I-N char ge-transfer (CT) complex that forms to different extent, depending on the flexibility of the scaffold. Under this condition, the molecules f old and apparently attain the correct conformation for competing subst ance P binding to the NK1 receptor, lending plausibility to the role o f dipolar charged, spatially close aromatic moieties as topochemical e lements in the mechanism of action of substance P antagonists. Tile ex cited-stare behavior parallels that in the ground state, as the quench ing of the singlet state at 340 nm is found to be linearly dependent o n the biological activity, too. Upon decreasing solvent polarity (meth anol vs dioxane) the emission of the dipolar state at around 370 nm di sappears, while exciplex emission in the range of 400-500 nm occurs. T his transition from charge-separated to exciplex-like states by loweri ng the dielectric constant of the medium very likely reflects a change in the structural features of the intramolecular I-N stacked complex, from a twisted or an asymetrically overlapped conformation of the ind olyl and naphthyl rings to a face-to-face geometry. Implications of th e rigidity of the molecules, arising from the formation of the intramo lecular CT complex, on the ellipticity are briefly discussed. (C) 1997 John Wiley & Sons, Inc.