We have recently reported the potent @entity14645 effects of side-chain @entity17272 -bridged analogues of @entity1 calcitonin (hCT) (Kapurniotu, A.; et al. Eur. J. Biochem. 1999, 265, 606-618). To extend these studies, we have now synthesized a new series of ( @entity2574 (17), Lys(21)) and ( @entity2574 (17), Orn(21)) side-chain bridged salmon calcitonin (sCT) and hCT analogues. The affinities of these analogues for the @entity1 calcitonin receptor, hCTR(I1)(-), and for @entity35 -brain membrane receptors were assayed in competitive binding assays, and agonist potencies at the hCTR(I1)(-) receptors were assessed, using a @entity268 -responsive gene-reporter assay. The bridged sCT analogues had activities similar to sCT itself. In contrast, an ( @entity2574 (17), Orn(21)) side-chain bridged hCT analogue, cyclo(17-21)-[Nle(8), @entity815 (12), @entity2574 (17), Orn,(21) Tyr(22))-hCT, was 80 and 450 times more active than hCT in the hCTR(I1)(-) and @entity35 -brain receptor binding assays, respectively, and was 90 times more potent than hCT and 16 times more potent than sCT in initiating receptor signaling. An uncyclized, isosteric analogue of this peptide was also more potent than hCT, demonstrating that the cyclization constraint and these single-residue substitutions enhance the activities of hCT in an additive fashion. This study demonstrates that the potency-enhancing effects of @entity17272 -bridge constraints at hCT residues 17-21 are not transferable to sCT. We also show that, in comparison to the hCT analogues, sCT and its analogues are less potent agonists than expected from their hCTR(I1)(-) affinities. This suggests that it may be possible to preserve the efficient signal transduction of hCT while introducing additional receptor affinity-enhancing elements from sCT into our potent @entity17272 -bridged hCT analogue, thereby creating new super-potent, hCT-based agonists.

Side-chain @entity17272 -bridge conformational constraints differentiate the activities of salmon and XXXX calcitonins and reveal a new design concept for potent calcitonin analogues.

@entity1 :: ('9606', 'Species') :: ['human'] @entity268 :: ('CHEBI:17489', 'Chemical') :: ['cAMP'] @entity14645 :: ('MESH:C562689', 'Disease') :: ['hypocalcemic'] @entity35 :: ('10116', 'Species') :: ['rat'] @entity17272 :: ('CHEBI:24995', 'Chemical') :: ['lactam'] @entity815 :: ('CHEBI:28044', 'Chemical') :: ['Phe'] @entity2574 :: ('CHEBI:22660', 'Chemical') :: ['Asp']
@entity1 :: (9606,Species) :: ['human']
