STRUCTURE-ACTIVITY AND CONFORMATIONAL STUDIES OF A SERIES OF MODIFIEDC-TERMINAL HEXAPEPTIDE NEUROTENSIN ANALOGS

Neurotensin (NT), is a linear tetradecapeptide Glu(4)-Asn(5)-Lys(6)-Pr o(7)-Arg(8)-Arg(9)-Pro(10)- Tyr(11)-IIe(12)-Leu(13)) that has been fou nd in the central nervous system and peripheral tissues and appears to have a variety of physiological properties. A C-terminal hexapeptide analogue [N(2)Me-Arg-Lys-Pro-Trp-Tle-Leu, (1) Tle = tert-leucine] has recently been reported to have high affinity for the NT receptor and a ppears to possess central activity after systemic administration. In a n effort to probe the structure-activity and conformational properties of the dipeptide, Pro-Trp for binding and functional activity, these residues have been substituted with several natural and unnatural amin o acids. Some of these analogues have binding affinities similar to co mpound 1, while in other cases, such as D-amino acid substitutions, th e peptides had negligible binding affinity. In general, the Pro(10) po sition seems more tolerant of substitution by amino acids that favor a reverse turn, rather than those that favor an extended conformation. The Trp(11) position accepted extra steric bulk more readily than conf ormational constraints. (C) Munksgaard 1994.