67198-53-2Relevant academic research and scientific papers
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.
Dynamic kinetic resolution allows a highly enantioselective synthesis of cis-α-aminocycloalkanols by ruthenium-catalyzed asymmetric hydrogenation
Liu, Sheng,Xie, Jian-Hua,Wang, Li-Xin,Zhou, Qi-Lin
, p. 7506 - 7508 (2008/09/17)
(Chemical Equation Presented) Resolutely dynamic hydrogenation: A highly efficient asymmetric hydrogenation of racemic N,N-disubstituted α-aminocycloalkanones involving dynamic kinetic resolution in the presence of a ruthenium catalyst gives chiral α-aminocycloalkanols with excellent enantioselectivities and cis diastereoselectivities (see scheme). A synthesis of optically pure U-(-)-50488 based on this reaction is reported.
Chemoenzymatic preparation of optically active trans-cyclohexane-1,2- diamine derivatives: An efficient synthesis of the analgesic U-(-)-50,488
Gonzalez-Sabin, Javier,Gotor, Vicente,Rebolledo, Francisca
, p. 5788 - 5794 (2007/10/03)
Stereoespecific syntheses of (±)-trans-N,N-cyclohexane-1,2-diamines ((±)-4a-g) were carried out from the corresponding (±)-trans-N,N- dialkylaminocyclohexanols by successive treatment with mesyl chloride and aqueous ammonia. The stereochemical outcome indicates the formation of a meso-aziridinium ion intermediate, Kinetic resolutions of diamines (±)-4 were efficiently accomplished in aminolysis reactions catalyzed by lipase B from Candida antarctica with ethyl acetate as the solvent and acyl donor. Acetamides and the remaining diamines, isolated as the benzyloxycarbonyl derivatives, were obtained with very high ee values (92-99%), One of the carbamates was used as a precursor of the analgesic U-(-)-50,488.
N-Methyl-N--1-phenylcyclopropanecarboxylic amides - analogs of U50488 with much reduced opiate affinity and loss of κ-selectivity
Cheng, CY,Lu, HY,Lee, FM
, p. 125 - 128 (2007/10/02)
(+/-)-N-methyl-N--1-phenylcyclopropanecarboxylic amide (1) and its dichloro analog (2) were synthesized.Compounds 1 and 2 are related to the κ-selective opiate U-50488 in that the benzylic methylene moiety in U-50488 has been replaced by a cyclopropane ring.As compared to U-50488, a 600-fold reduction in kappa-affinity was observed with these 2 compounds; while the reduction in μ-affinity was less than 2-fold.Unlike U-50488, 1 and 2 also show measurable δ-binding.To explain the observed anomaly, the steric interaction between the N-methyl group and the cyclopropane ring and the tendency of the cyclopropane ring to conjugate with the neighboring phenyl group, both affecting the accessible conformations of the amide side chains of 1 and 2, are cosidered important factors.
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.
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.
SUBSTITUTED NAPHTHALENYLOXY-1,2-DIAMINOCYCLOHEXYL AMIDE COMPOUNDS
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, (2008/06/13)
Substituted naphthalenyloxy-or naphthalenylthiooxyamides of trans-1,2-diaminocyclohexanes possess selective kappa opioid receptor site binding activity and are thus useful as analgesic or diuretic agents. Methods of preparing the compounds, pharmaceutical compositions, and a method for their use as analgesic agents are also disclosed.
SUBSTITUTED TRANS-1,2-DIAMINOCYCLOHEXYL AMIDE COMPOUNDS
-
, (2008/06/13)
Substituted trans-1,2-diaminocyclohexyl amide compounds demonstrating selective opioid receptor binding possess utility as analgesic, diuretic, and psychotherapeutic agents. A method of preparing the compounds, pharmaceutical compositions employing the co
Substituted trans-1,2-diaminocyclohexyl amide compounds
-
, (2008/06/13)
Substituted trans-1,2-diaminocyclohexyl amide compounds demonstrating selective opioid receptor binding possess utility as analgesic, diuretic, and psychotherapeutic agents. A method of preparing the compounds, pharmaceutical compositions employing the co
