Michael Higginbottom

α-Methyl tryptophanylphenylalanines and their arylethylamine “dipeptoid” analogues of the tetrapeptide cholecystokinin (30–33)

Abstract A series of N -alkyl carbamate blocked α-Me-Trp-Phe and α-Me-Trp-phenethylamides has been identified as “dipeptoid” analogues of CCK - 4 (CCK 30–33). These compounds have micromolar affinity for the type-B central CCK receptor, some of which increase the firing rate of CCK-B rich neurons in isolated slices containing the ventro-medial nucleus (VMN) of the hypothalamus from rat brain. SAR studies indicate that the preferred N -substituents are bulky groups such as Boc-, Amoc-, Adoc and TcBoc-, and that d -α-Me-Trp and l -Phe configurations are preferred. The C -terminal phenyl group can be replaced by substituted phenyl and selected heteroaryl groups such as 2-thienyl and 2-pyridyl. The C -terminal amide group can be replaced by -CH 2 OH, -CO-piperidide, and even -H without loss of binding affinity e.g. Boc- dl -α-Me-Trp-CH 2 CH 2 Ph as K i of 11 μM. These small non-peptide molecules have comparable receptor affinities to certain full tetrapeptide analogues of CCK -4 and compound 24 , TcBoc- dl -α-McTrp-phenylethylamide, is the first CCK - dipeptoid with CCK - B like agonist properties so far described.

Rationally designed dipeptoid' analogues of cholecystokinin (CCK): N-terminal structure-affinity relationships of α-methyl-tryptophan derivatives

Abstract This paper outlines the synthesis and C-terminal structure-activity relationships (SAR) of a series of α-methyl tryptophanylphenethylamide analogues of the neuropeptide cholecystokinin (CCK). CCK-B and CCK-A receptor binding affinities of these analogues are described and the contributions of the various side chains on the phenethylamide moiety to binding affinity are discussed. Several of the compounds prepared have CCK-B receptor binding affinities similar to that found with the endogenous neuropeptide CCK-26-33 (sulphated) (CCK-B, IC 50 = 0.3 nM) and are highly selective over the CCK-A receptor. Amongst the most potent of the compounds synthesized are [ R -( R ∗ , S ∗ )]-β-[[3-(1 H -indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1 3,7 ]dec-2-yloxy )carbonyl]amino]propyl]amino]benzenebutanoic acid 22 , [ R -( R ∗ , S ∗ )]-[[2-[[3-(1 H -indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1 3,7 ]dec-2-yloxy)carbonyl] amino]propyl]amino]-3-phenylpropyl] thio]acetic acid 28a and [ R -( R ∗ , S ∗ )]-[[2-[[3-(1 H -indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1 3,7 ]dec-2-yloxy) carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]acetic acid 32 which have CCK-B receptor binding affinities of IC 50 = 0.3, 0.3 and 0.2 nM with CCK-A/B ratios of 220, 700 and 1000, respectively. CCK-B receptor selective ligands, 22, 28a and 32 were also shown to be potent antagonists in blocking pentagastrin-evoked excitation in neurons of the rat hypothalamic ventro-medial nucleus (VMN) with the K e values of 2.8, 23 and 5.9 nM, respectively.

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.

Conformationally restricted analogues of the potent CCK-B antagonist CI-988

The synthesis and structure-activity relationships (SAR) for a series of conformationally restricted analogues of the selective cholecystokinin (CCK) antagonist CI-988 and some closely related analogues are described. A series of appropriately substituted cis- and trans-amino decalins are prepared that mimic the through bond distances between the functional groups in the parent compound CI-988 whilst restricting bond rotation. This strategy has led to conformationally more rigid derivatives that have increased CCK-B receptor binding affinity.