Analogues of human calcitonin. IV. Influence of leucine substitutions in positions 12, 16 and 19 on hypocalcaemic activity in the rat.
The replacement of the three aromatic amino acids in positions 12, 16 and 19 of human calcitonin (HCT) by leucine residues, which occupy the corresponding positions, in ultimobranchial, e.g. salmon and eel, calcitonins, increased the hypocalcaemic potency of the peptide, as determined by bioassay on the rat, about 10-fold. The individual substitutions were not all equally augmentative: leucine (12) enhanced the activity of HCT about 4--5 times, but leucine (16) and (19) afforded no increase at all. Combination of leucine (12) with a deamino cysteine at the N-terminus yielded an analogue 10 times more potent than HCT. Another analogue containing valine in position 8 in place of methionine as well as the three leucine substituents in position 12, 16 and 19 proved more active than the tri-leucine analogue, but the additional introduction of tyrosine (22) nearly doubled the hypocalcaemic potency of the latter. The duration of the hypocalcaemic effects of the substituted peptides closely followed the changes in potency.
D000595:Amino Acid Sequence; D000818:Animals; D002116:Calcitonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000097:blood*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007930:Leucine / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors
D002116:Calcitonin; D007930:Leucine; D002118:Calcium