118243-30-4Relevant academic research and scientific papers
Probes for Narcotic Receptor Mediated Phenomena. 17. Synthesis and Evaluation of a Series of trans-3,4-Dichloro-N-methyl-N-benzeneacetamide (U50,488) Related Isothiocyanate Derivatives as Opioid Receptors Affinity Ligands
Costa, Brian R. de,Rothman, Richard B.,Bykov, Victor,Band, Linda,Pert, Agu,et al.
, p. 1171 - 1176 (2007/10/02)
A series of U50,488 related isothiocyanates was synthesized from enantiomerically pure (S,S)-(+)-trans-2-pyrrolidinyl-N-methylcyclohexylamine and (R,R)-(-)-trans-2-pyrrolidinyl-N-methylcyclohexylamine .DCC coupling of (+)- and (-)-7 with nitrophenylacetic acids followed by catalytic hydrogenation and treatment with thiophosgene afforded a series of six isomeric aryl isothiocyanate analogues of U50,488.Similarly, DCC coupling of (+)- and (-)-7 with (+)- and (-)-N-t-Boc-protected phenylglycines afforded four isomeric alkyl isothiocyanates.Evaluation ofthe isothiocyanates for their capacity to produce wash-resistant inhibition of μ, δ, and κ sites in vitro was performed using rat and guinea pig brain membranes.None of the compounds was able to irreversibly inhibit binding of bremazocine to guinea pig and rat brain membranes (depleted of functional μ and δ receptors by pretreatment with acylating agents BIT and FIT).However, (1S,2S)-trans-2-isothiocyanato-N-methyl-N-benzeneacetamide was able to specifically and irreversibly inhibit κ receptors labeled by -U69,593: Incubation of rat brain membranes for 60 min at 25 deg C with 1 μM of (-)-1 resulted in a wash-resistant reduction of the binding to 11.2 +/- 2.5percent of the control.Binding analysis revealed the wash-resistant reduction in -U69,593 binding by (-)-1 to be through an increase in the Kdwithout effect on the Bmax. (-)-1 failed to effect μ or δ binding in rat or guinea pig under the same conditions.The enatiomer of (-)-1, (1R,2R)-trans-2-isothiocyanato-N-methyl-N-benzeneacetamide , failed to affect κ receptors labeled by-U69,593 under the same conditions as for (-)-1. (1S,2S)-trans-3-Isothiocyanato-N-methyl-N-benzeneacetamide inhibited to 49.6 +/- 5.1percent of the control, in a wash-resistant manner, κ receptors labeled by -U69,593.However, (-)-2 was not as selective as (-)-1 since it also reduced DADLE (δ) binding to 82.4 +/-8.9percent of the control value. (1S,2S)-trans-4-Isothiocyanato-N-methyl-N-benzeneactamide exhibited selective wash-resistant inhibition of δ receptors labeled by DADLE resulting in a reduction in binding to 42.9 +/- 4.2percent of control.In the alkyl isothiocyanate series, (1S,2S)-trans-N-methyl-N--(S)-2-phenyl-2-isothiocyanatoaceatmide also showed the capacity to selectively inhibit -U69,593-sensitive κ sites, resulting in a reduction in binding to 72,2 +/- 2.54percent of control at 1 μM while (+)-11 was inactive.None of the amino precursors (-)-8, (+)-8, (-)-9, (+)-9, (-)-10, (+)-10, (-)-15, (+)-15, (-)-16, and (+)-16 of the isothiocyanates exhibited the capacity for wash-resistant inhibition of any of the receptor systems tested. ...
