Combination of cyclohexane and piperazine based κ-opioid receptor agonists: Synthesis and pharmacological evaluation of trans,trans-configured perhydroquinoxalines.

Abstract Desymmetrization of the pseudochiral (2 r )-configured cyclohexane-1,2,3-triamines 8 with dimethyl oxalate led to racemic aminoquinoxaline-2,3-diones 9 . Selective introduction of the κ pharmacophoric structural elements pyrrolidine and 3,4-dichlorophenylacetamide with a two-carbon distance afforded conformationally restricted κ agonists 13 – 15 based on the quinoxaline ring system. In competitive radioligand receptor binding studies the benzylamine 13b , the secondary amine 14b , and the carbamate 15 displayed high κ receptor affinity. The K i value of the lead compound derived methoxycarbonyl derivative 15 is 9.7 nM. However, the κ affinity of 15 is exceeded by 13b and 14b with a basic functional group instead of the methoxycarbonyl group in 1-position of the quinoxaline system. The chlorine atoms of the dichlorophenylacetyl residue are essential, since the corresponding phenylacetyl analogs show considerably reduced κ affinity. The potent κ ligands 13b , 14b and 15 are selective over the related μ- and δ-opioid receptors, σ 1 , σ 2 and NMDA receptors. In the [ 35 S]GTPγS-binding assay 13b behaved as partial agonist with lower activity than U-69,593.