The C- and N-terminal residues of synthetic heptapeptide ion channels influence transport efficacy through phospholipid bilayers

The synthetic peptide, R2N-COCH(2)OCH2CO-Gly-Gly-Gly-Pro-Gly-Gly-Gly-OR', was shown to be selective for Cl- over K+ when R is n-octadecyl and R' is benzyl. Nineteen heptapeptides have now been prepared in which the N-terminal and C-terminal residues have been varied. All of the N-terminal residues are dialkyl but the C-terminal chains are esters, 2degrees amides, or 3degrees amides. The compounds having varied N-terminal anchors and C-terminal benzyl groups are as follows: 1, R n-propyl; 2, R n-hexyl; 3, R n-octyl; 4, R n-decyl; 5, R n-dodecyl; 6, R n-tetradecyl; 7, R n-hexadecyl; 8, R n-octadecyl. Compounds 9-19 have R n-octadecyl and C-terminal residues as follows: 9, OR' = OCH2CH3; 10, OR' = OCH(CH3)(2); 11, OR' = O(CH2)(6)CH3; 12, OR' = OCH2-c-C6H11; 13, OR' = O(CH2)(9)CH3; 14, OR' = O(CH2)(17)CH3; 15, NR2' = N[(CH2)(6)CH3](2); 16, NHR' = NH(CH2)(9)CH3; 17, NR2' = N[(CH2)(9)CH3](2); 18, NHR' = NH(CH2)(17)CH3; 19, NR2' = N[(CH2)(17)CH3](2). The highest anion transport activities were observed as follows. For the benzyl esters whose N-terminal residues were varied, i.e. 1-8, compound 3 was most active. For the C-18 anchored esters 10-14, n-heptyl ester 11 was most active. For the C-18 anchored, C-terminal amides 15-19, di-n-decylamide 17 was most active. It was concluded that both the C- and N-terminal anchors were important for channel function in the bilayer but that activity was lost unless only one of the two anchoring groups was dominant.