A NEW CLASS OF HIGH-AFFINITY LIGANDS FOR THE NEUROKININ-A NK2 RECEPTOR - PSI(CH2NR) REDUCED PEPTIDE-BOND ANALOGS OF NEUROKININ-A4-10

Analogues of [Leu10]NKA4-10 were synthesized in which each of the amide bonds was sequentially replaced with the reduced amide psi(CH2NH) bond to determine the effect of this structural modification on the antagonism of NKA binding to the HUB NK2 receptor. [psi(CH2-NH)9,Leu10]NKA4-10 (6) retained significant affinity for the NK2 receptor (IC50=115 nM) and showed weak partial stimulation of PI turnover (approximately 10-15% of NKA maximum). 6 behaves as a competitive antagonist of NKA-stimulated PI turnover with a pA2=6.7. The secondary amine of the psi(CH2NH) moiety of 6 was converted to a tertiary amine by alkylation. This modification was found to have a small effect upon receptor affinity but did result in attenuation of partial agonist activity. A combination of amino acid substitutions and psi(CH2NH) alkylation yielded [betaAla8,psi(CH2N(CH2)2CH3)9,Phe10]NKA4-10 (21) which has very high affinity for the HUB NK2 receptor. This compound inhibited [I-125]NKA binding with an IC50=1 nM which is equal to the receptor affinity of NKA. Compound 21 also shows very weak partial agonism of PI turnover (less-than-or-equal-to 5% of NKA maximum) which makes this the most potent member of a new class of NKA ligands: psi(CH2NR)9-NKA4-10 analogues which potently antagonize NKA binding and possess minimal partial agonist activity.