Giles S. Ratcliffe

The design of dipeptide helical mimetics: The synthesis, tachykinin receptor affinity and conformational analysis of 1,1,6-trisubstituted indanes

The design and synthesis of conformationally constrained, nonpeptide templates (1,1,6-trisubstituted indanes) which allow the incorporation of two adjacent amino acid side chains, plus a third binding group in an orientation similar to that found in alpha-helices are reported. Six racemic and two homochiral Phe-Phe and Trp-Phe mimetics were synthesised and evaluated in tachykinin receptor binding assays as molecular probes for the binding conformation of the endogenous peptides. Several were found to bind with micromolar affinity to the NK1 and/or NK3 receptor. The conformation of one of the homochiral indanes, (1R)-N-((S)-1-hydroxymethylbenzyl)-1,6-dibenzylindan-1-carbo xamide, was analysed by X-ray crystallography and was found to be in an alpha-helix conformation.

The rational development of small molecule tachykinin NK3 receptor selective antagonists - the utilisation of a dipeptide chemical library in drug design

Abstract Boc(S)Phe(S)PheNH2 (1c) was identified from the biological screening of an in-house dipeptide chemical library as a micromolar NK3 receptor selective ligand (IC50=1150nM). This lead structure has subsequently been developed into a series of potent and selective NK3 receptor antagonists an example of which is the urea derivative Boc(S)Phe(R)αMePheNH(CH2)7NHCOHNH2 (11d, PD157672) (IC50=16nM).

An in vitro investigation into conformational aspects of gabapentin.

Conformational analysis of constrained cyclohexane systems was pioneered fifty years ago by Barton and Hassel. We now report an investigation based on a conformational analysis of a number of novel cyclohexane based Gabapentin analogues coupled with their in vitro evaluation at the Gabapentin binding site. These data are used to propose a possible binding conformation for Gabapentin.

The design of a dipeptide library for screening at peptide receptor sites

Abstract A physico-chemical information rich library of 256 N-protected dipeptides is described. This library has been constructed using a factorial design in the principal properties of the amino acids. These compounds represent a data set of diverse physical properties which can be screened against a variety of protein substrates in binding assays in the search for micromolar chemical leads for drug design. The concept is supported by the design of CCK-A and -B non-peptide ligands from the dipeptide lead Boc-Trp-Phe-NH2, a non-contiguous dipeptide fragment of CCK.

The synthesis of 1,6-disubstituted indanes which mimic the orientation of amino acid side-chains in a protein alpha-helix motif.

Abstract We utilize a 1,6-disubstituted indane as a template onto which two amino acid side-chains are appended in an orientation which mimics that found in a protein alpha-helix motif.

The Use of Heterocycles for the Conformational Restriction of Biologically Active Peptoids

Abstract A series of piperazinone ring systems have been synthesised as a means of evaluating the effect of conformational restriction on high affinity non-peptide NK1, NK3 and CCK-B receptor ligands. The synthesis of the targeted heterocycles is described along with a discussion of their affinities for their respective receptor types.

The design of dipeptide helical mimetics, Part I: the synthesis of 1,6-disubstituted indanes

Abstract The design and synthesis of conformationally restrained, non-peptide templates (1,6-disubstituted indanes) which allow the incorporation of two adjacent amino acid side-chains in an orientation similar to that found in alpha-helices is reported.

Stabilities of tryptophanylpnenethylamides to acid and alkaline conditions.

Abstract The stability of various alkyloxycarbonyl-α-methyl-tryptophanylphenethylamines in acid media and their decomposition to hydantoins in basic media re discussed.

The use of a proline ring as a conformational restraint in CCK-B receptor “dipeptoids”.

Abstract Examination of molecular dynamics simulations and an X-ray crystal structure of a selective CCK-B receptor dipeptoid Trp derivative led to the synthesis of a conformationally restrained Pro derivative. The CCK receptor binding of this target compound ( 7 ) is described.

The design and synthesis of kappa opioid ligands based on a binding model for kappa agonists

Abstract The chemical structures of known kappa opioid receptor agonists are used in a modelling study to propose a binding model for kappa ligands. Based on this model three novel non-peptide structures are synthesised and one compound (8) has kappa receptor K1 = 160 nM, mu K1 > 10000 nM.