ANALOGS OF THE C-TERMINAL FRAGMENTS OF NEUROKININS WITH MODIFICATIONSAT THEIR C-TERMINAL METHIONYL RESIDUE - STRUCTURE-ACTIVITY STUDIES

Analogues of SP4-11 have been synthesized in which the methionyl resid ue is replaced successively by the Glu(OCH2CH3), Glu(OBzl), Hse(CH3) a nd Glu(CONHCH3) residues, and analogues of NKA(4-10) and NKB4-10 have been prepared in which the methionyl residue is replaced by the Hse(Bz l) and Hse(CH3) residues, respectively. The SP4_11 analogues were test ed in three in vitro o preparations representative of NK-1, NK-2 and N K-3 receptor types. Substitution of the SCH3 group of the Met(11) side chain by the groups COOCH2CH3 and COOBzl has little affect on the ago nist activity in NK-1 preparations, while in NK-2 the corresponding an alogues are more potent than the parent octapeptide; that substituted with COOBzl being 8.2 times more potent than SP4_11, In NK-3 preparati ons all analogues are weak agonists. The selectivity of all the analog ues is reduced compared with the corresponding hexapeptide analogues. The SP4-11 analogues, along with those of NKA(4_10) and NKB4-10, were tested for their binding ability in the three receptor subtypes above. The SP4_11 analogues show reduced affinity for NK-1 receptors, while the NKA(4-10) and NKB4-10 analogues have almost the same affinities as NKA and NKB for NK-2 and NK-3 receptors, respectively. The effect of the lipophilicity of the Met(11) side chain, especially when a phenyl group is present in the side chain, at the NK-2 receptor is discussed. (C) Munksgaard 1994.