130553-66-1Relevant 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.
experimental part, 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.
Synthesis and evaluation of N-substituted cis-N-methyl-2-(1-pyrrolidinyl)cyclohexylamines as high affinity σ receptor ligands. Identification of a new class of highly potent and selective σ receptor probes
De Costa,Rice,Bowen,Thurkauf,Rothman,Band,Jacobson,Radesca,Contreras,Gray,Daly,Iyengar,Finn,Vazirani,Walker
, p. 3100 - 3110 (2007/10/02)
Certain benzeneacetamides [(-)- and (+)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzenea cetamide] were recently reported to be potent σ receptor ligands. In order to determine whether efficacy for the σ receptor could be improved, a series of compounds related to the benzeneacetamides, N-substituted cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines, were synthesized and their structure-activity requirements were determined. The compounds were synthesized by starting with the previously reported (±)-, 1S,2R-(+)-, and 1R,2S-(-)-cis-2-(1-pyrrolidinyl)-N-methylcyclohexylamines. Analysis of σ ([3H](+)-3-PPP), κ ([3H]bremazocine and [3H]U69,593), dopamine-d2 ([3H](-)-sulpiride), and phencyclidine (PCP) ([3H]TCP) receptor binding in guinea pig brain revealed a number of highly potent and selective σ receptor ligands. Notably, 1S,2R-cis-(-)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(2-naphthyl)ac etamide [(-)-29] (K(i) = 8.66 ± 0.35 nM), (±)-cis-2-amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl ]benzeneacetamide [(±)-17] (K(i) = 11 ± 3 nM), 1S,2R-(-)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidin yl)cyclohexylamine [(-)-44] (K(i) = 1.3 ± 0.3 nM), and 1R,2S-(+)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidin yl)cyclohexylamine. [(+)-44] (K(i) = 6 ± 3 nM) exhibited very high affinity at σ receptors, by displacement of [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H]-(+)-3-PPP). These compounds showed significant affinity for κ, dopamine, or PCP receptors, making them valuable tools for the study of σ receptors. Furthermore, these compounds also exhibited enantioselectivity ranging from 5-fold for (+)- and (-)-44 to 160-fold for (+)- and (-)-29. Several other compounds showed equivalent selectivity but displayed lower σ receptor affinity.
