67347-43-7Relevant 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.
Alterations in the stereochemistry of the κ-selective opioid agonist U50,488 result in high-affinity σ ligands
De Costa,Bowen,Hellewell,George,Rothman,Reid,Walker,Jacobson,Rice
, p. 1996 - 2002 (2007/10/02)
The synthesis and in vitro σ receptor activity of the two diastereomers of U50,488 [(±)-2], namely (1R,2S)-(+)-cis-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide [(+)-1], and (1S,2R)-(-)-cis-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-1], are described. (+)-1 and (-)-1 were synthesized from (±)-trans-N-methyl-2-aminocyclohexanol [(±)-3]. Pyridinium chlorochromate (PCC) oxidation of the N-t-Boc-protected derivative of (±)-3 afforded (±)-2-[N-[(tert-butyloxy)carbonyl]-N-methylamino]cyclohexanone [(±)-5]. The sequence of enamine formation with pyrrolidine, catalytic reduction, N-deprotection, and optical resolution afforded (1R,2R)-(-)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-10] and (1S,2R)-(+)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-10]. The optical purity (>99.5%) of (-)-10 and (+)-10 was determined by HPLC analysis of the diastereomeric ureas formed by reaction with optically pure (R)-α-methylbenzyl isocyanate. The absolute configuration of (-)-10 and (+)-10 was determined by single-crystal X-ray diffractometry of the bis-(R)-mandelate salt. Condensation of optically pure (-)-10 and (+)-10 with 3,4-dichlorophenylacetic acid furnished (+)-1 and (-)-1, respectively. Compounds (+)-1, (-)-1, (-)-2, and (+)-2 were compared for their binding affinities at κ opioid, σ, D2-dopamine, and phencyclidine (PCP) receptors in competitive binding assays using [3H]bremazocine ([3H]BREM) or [3H]U69,593, [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [[3H]-(+)-3-PPP], or [3H]-1,3-di(o-tolyl)guanidine ([3H]DTG), [3H]-(-)-sulpiride [[3H]-(-)-SULP], and [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP), respectively. In the systems examined, (-)-2 exhibited the highest affinity for κ receptors, with a K(i) of 44 ± 8 nM. However, (-)-2 also showed moderate affinity for σ receptors, with a K(i) of 594 ± 3 nM [[3H]-(+)-3-PPP]. The (1R,2S)-(+)-enantiomer, (+)-2, had low affinity for both κ and σ receptors, exhibiting K(i) values of 1298 ± 49 nM at κ ([3H]BREM) and 1270 ± 168 nM at σ [[3H]-(+)-3-PPP]. In contrast, the chiral cis compounds (+)-1 and (-)-1 showed high affinity for σ receptors and negligible affinity for κ opioid receptors in the [3H]BREM assay. Compound (-)-1 exhibited a K(i) of 81 ± 13 nM at σ receptors [[3H]-(+)-3-PPP] and 250 ± 8 nM ([3H]DTG). The corresponding values for (+)-1 were 221 ± 36 nM [[3H]-(+)-3-PPP] and 118 ± 7 nM ([3H]DTG). Compounds (-)-2 and (+)-2 lacked affinity for D2-dopamine receptors. Compounds (+)-1 and (-)-1 bound only weakly to D2-dopamine receptors, displaying K(i) values of 14039 ± 1429 nM and 3762 ± 829 nM, respectively. All of the compounds lacked affinity for PCP receptors.
