67198-34-9Relevant articles and documents
Optimisation of the Anti-Trypanosoma brucei Activity of the Opioid Agonist U50488
Smith, Victoria C.,Cleghorn, Laura A. T.,Woodland, Andrew,Spinks, Daniel,Hallyburton, Irene,Collie, Iain T.,YiMok,Norval, Suzanne,Brenk, Ruth,Fairlamb, Alan H.,Frearson, Julie A.,Read, Kevin D.,Gilbert, Ian H.,Wyatt, Paul G.
, p. 1832 - 1840 (2012/06/18)
Screening of the Sigma-Aldrich Library of Pharmacologically Active Compounds (LOPAC) against cultured Trypanosoma brucei, the causative agent of African sleeping sickness, resulted in the identification of a number of compounds with selective antiproliferative activity over mammalian cells. These included (+)-(1R,2R)-U50488, a weak opioid agonist with an EC50 value of 59nM as determined in our T.brucei invitro assay reported previously. This paper describes the modification of key structural elements of U50488 to investigate structure-activity relationships (SAR) and to optimise the antiproliferative activity and pharmacokinetic properties of this compound.
Highly selective κ-opioid analgesics. 2. Synthesis and structure-activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide derivatives
Halfpenny,Hill,Horwell,Hughes,Hunter,Johnson,Rees
, p. 1620 - 1626 (2007/10/02)
This paper describes the chemical synthesis and the development of structure-activity relationships (SAR) for the κ opioid receptor affinity and μ/κ opioid receptor selectivity of novel N-[(2-aminocyclohexyl)aryl]acetamide derivatives. The SAR of this series are investigated by consideration of structural modifications made to the aromatic moiety, the amide linkage, and cyclohexane and the pyrrolidine ring substituents of the prototype κ selective agonist, PD117302 (trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo[b]thiophene-4-act etamide) (1). The κ and μ opioid receptor binding affinities of 23 novel compounds are reported. It is observed that optimal μ/κ receptor selectivity is obtained with a benzo[b]thiophene aromatic system attached via the C-4 position, which is discussed in terms of steric and electronic parameters. The amide linkage has been replaced with the reversed amide, an ester, an aminomethylene, a thioamide, and a secondary amide. The best of these isosteres is the N-methyl amide. Substitution of the pyrrolidine ring of PD117302 in the 3-position with a hydroxymethylene group increases the μ/κ selectivity compared to the unsubstituted compound, e.g. compound 14, trans-(±)-N-methyl-N-[2-[3-(hydroxymethyl)-1-pyrrolidinyl]cyclo-hexylt ]-4-benzo[b]furanacetamide monohydrochloride, μ/κ receptor selectivity = 244. The cis fused, 4,5 dimethyl ether substituted cyclohexane analogue trans-(±)-N-methyl-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-bent zo[b]thiophene-4-acetamide monohydrochloride (32) has high in vitro κ opioid receptor affinity (K(i) = 16 nM) and equipotent analgesic activity to morphine after iv administration in rats.
