Towards a KCC2 blocker pharmacophore model.

A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.

Synthesis and biological evaluation of constrained analogues of the opioid peptide H-Tyr-D-Ala-Phe-Gly-NH2 using the 4-amino-2-benzazepin-3-one scaffold.

The synthesis of conformationally restricted dipeptidic moieties 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba)-Gly ([(4S)-amino-3-oxo-1,2,4,5-tetrahydro-1H-2-benzazepin-2-yl]-acetic acid) and 8-hydroxy-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Hba)-D-Ala ([(4S)-amino-8-hydroxy-3-oxo-1,2,4,5-tetrahydro-benzo[c]azepin-2-yl]-propionic acid) was based on a synthetic strategy that uses an oxazolidinone as an N-acyliminium precursor. Introducing these Aba scaffolds into the N-terminal tetrapeptide of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2)-induced remarkable shifts in affinity and selectivity towards the opioid mu- and delta-receptors. This paper provides the synthesis and biological in vitro and in vivo evaluation of constricted analogues of the N-terminal tetrapeptide H-Tyr-D-Ala-Phe-Gly-NH2, which is the minimal subunit of dermorphin needed for dermorphin-like opiate activity.

Conformational restriction of Tyr and Phe side chains in opioid peptides: information about preferred and bioactive side-chain topology.

The side chain of Tyr and Phe was fixed into the gauche(-) or gauche(+) conformation by using the Tic Htc structures, and into the trans conformation by using an aminobenzazepine-type (Aba) structure. When incorporated into dermorphin or deltorphin II, the Tic and Htc analogues all showed a large decrease in both mu and delta affinities and activities. Fixation of Phe(3) in the trans rotamer resulted in a large increase in delta affinity in the dermorphin analogue, whereas in the [Aba(3)-Gly(4)] deltorphin II analogue, good delta affinity is maintained despite the removal of the Glu side chain.