294625-14-2Relevant articles and documents
Nonpeptide analogues of dynorphin A(1-8): Design, synthesis, and pharmacological evaluation of κ-selective agonists
Ronsisvalle,Pasquinucci,Pittala,Marrazzo,Prezzavento,Di Toro,Falcucci,Spampinato
, p. 2992 - 3004 (2007/10/03)
Two novel series of κ opioid receptor agonist analogues of MPCB-GRRI and MPCB-RRI, hybrid ligands ofMPCB ((-)-cis-N-(2-phenyl-2-carbomethoxy)cyclopropylmethyl-N-normetazo cine) and of the C-terminal fragments of dynorphin A(1-8), have been synthesized. The critical functional groups of the peptide fragments of hybrid compounds were maintained, and the binding affinities and selectivities for compounds 1-40 to μ, δ, and κ opioid receptors were analyzed. Compounds 15 and 16, MPCB-Gly-Leu-NH-(CH2)(n)-NH-C( = NH)-C4H9 (n = 5, 6), displayed high affinity and selectivity for κ opioid receptors (K(i)(κ) = 6.7 and 5.3 nM, K(i)(μ)/K(i)(κ) = 375 and 408, and K(i)(δ)/K(i)(κ) = 408 and 424, respectively). Since κ agonists may also cause psychotomimetic effects by interaction with σ sites, binding assays to σ1 sites were performed where compounds 15 and 16 showed negligible affinity (K(i) > 10 000). Compounds 15 and 16 were further characterized in vivo and showed potent antinociceptive activity in mouse abdominal constriction tests (ED50 = 0.88 and 1.1 mg/kg, respectively), fully prevented by nor-BNI. Thus, these novel analogues open an exciting avenue for the design of peptidomimetics of dynorphin A(1-8).
