D A Tocher

Publications (3)14.19 Total impact

• Article: A novel synthesis of (di)-benzazocinones via an endocyclic N-acyliminium ion cyclisation.

  Frank D King, Abil E Aliev, Stephen Caddick, D A Tocher
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  ABSTRACT: The triflic acid-mediated endocyclic N-acyliminium ion cyclisation provides a facile synthesis of (di)-benzazocinones. On reduction of the 10-phenyl derivative, an unusually non-polar tertiary alkylamine was obtained.
  Organic & Biomolecular Chemistry 03/2011; 9(5):1547-54. · 3.70 Impact Factor
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  Available from: Muy-Teck Teh

  Article: Mapping the melatonin receptor. 5. Melatonin agonists and antagonists derived from tetrahydrocyclopent[b]indoles, tetrahydrocarbazoles and hexahydrocyclohept[b]indoles.

  D J Davies, P J Garratt, D A Tocher, S Vonhoff, J Davies, M T Teh, D Sugden
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  ABSTRACT: Tetrahydrocyclopent[b]indoles, tetrahydrocarbazoles, and hexahydrocyclohept[b]indoles have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was compared in a radioligand binding assay using chicken brain membranes and agonist and antagonist potency measured in clonal Xenopus laevis melanophore cells. Comparison of the N-acyl-3-amino-6-methoxytetrahydrocarbazoles (2) with N-acyl-4-(aminomethyl)-6-methoxy-9-methyltetrahydrocarbazoles (9) showed that the latter have much higher binding affinities for the chicken brain receptor. Comparison of N-acyl-1-(aminomethyl)-7-methoxy-4-methyltetrahydrocyclopent[b]ind oles (10), 6-methoxytetrahydrocarbazoles (9), and N-acyl-10-(aminomethyl)-2-methoxy-5-methylhexahydrocyclohept[b]ind oles (11) showed that the tetrahydrocarbazoles had the highest binding affinity with the cyclohept[b]indoles and the cyclopent[b]indoles having rather lower affinities. All of these observations are in agreement with our postulated model of melatonin orientation at the binding pocket in which the 3-amidoethane side chain is in a conformation close to the 5-methoxyl group, as is shown in the X-ray crystallographic structure of 9m and in the energy-minimized computed structures. Separation of the enantiomers of members from each of these three systems was accomplished by chiral HPLC. It was found that in all cases the (-)-enantiomer had a higher binding affinity than the (+)-enantiomer. An X-ray crystallographic analysis of the two enantiomers of 9a showed that the (+)-enantiomer had the (R) absolute stereochemistry. Since the sign of the Cotton curves, determined from circular dichroism studies, was the same for all (+)-enantiomers, it is assumed that the absolute stereochemistry at these centers is identical. In the Xenopus melanophore assay, the tetrahydrocarbazoles 2 (R = H) were mainly weak antagonists, while those with R = OMe were agonists. The biological behavior of the tetrahydrocarbazoles 9 (R = H) depended on R1, some being agonists and some antagonists, whereas those with R = OMe were generally agonists. Variation of the R and R1 groups in compounds of type 9 produced both agonists and antagonists. The tetrahydrocylopentaindoles 10 had similar biological properties to the corresponding analogues of 9, but the hexahydrocycloheptaindoles 11 showed a much greater propensity to be antagonists. In all cases the (S)-enantiomers were found to be more potent agonists than the (R)-enantiomers.
  Journal of Medicinal Chemistry 03/1998; 41(4):451-67. · 5.25 Impact Factor
• Article: Mapping the melatonin receptor. 3. Design and synthesis of melatonin agonists and antagonists derived from 2-phenyltryptamines.

  P J Garratt, R Jones, D A Tocher, D Sugden
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  ABSTRACT: Three series of 2-phenyltryptamides were prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor in chicken brain and in Xenopus laevis melanophore cells. The 5-methoxy-2-phenyltryptamides (6a-j) have high binding affinities for the chicken brain receptor, in some cases (6a-d) greater than that for melatonin, confirming and extending the work of Spadoni et al., and act as agonists in the Xenopus melanophore assay. Analogues lacking the 5-methoxyl group (2a-n) had a considerably lower affinity for the chicken brain receptor. In the Xenopus melanophore assay the compounds acylated on nitrogen by an alkyl group (2a-d) were agonists whereas the compounds acylated on nitrogen by an alicyclic group (2f-i) were antagonists. Introducing a methyl group at N1 (7) led to an increase in binding affinity in the chicken brain assay, whereas introducing an ethyl group (13) led to a decrease in binding affinity. A methyl substituent at the beta-position of the 3-amidoethane side chain (8, 11) also led to an increase in the binding affinity. The only analogue acylated on nitrogen with an alkyl group (acetyl) which showed antagonist activity was 9, which has a beta-methoxymethyl side chain. In the absence of the 5-methoxyl group the methoxymethyl function may cause the molecule to bind in a different configuration so that it is no longer able to activate the receptor. All of these observations are in agreement with a model of melatonin at the receptor site in which the 3-amidoethane side chain is in a conformation close to the 5-methoxyl group.
  Journal of Medicinal Chemistry 04/1995; 38(7):1132-9. · 5.25 Impact Factor