Nonpeptide analogues of dynorphin A(1-8): Design, synthesis, and pharmacological evaluation of k-selective agonists

Two novel series of kappa opioid receptor agonist analogues of MPCB-GRRI an d MPCB-RRI, hybrid ligands of MPCB ((-)-cis-N-(2-phenyl-2-carbomethoxy)cycl opropylmethyl-N-normetazocine) and of the C-terminal fragments of dynorphin A(1-8), have been synthesized. The critical functional groups of the pepti de fragments of hybrid compounds were maintained, and:the binding affinitie s and selectivities for compounds 1-40 to mu, delta, and kappa opioid recep tors 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 kappa opioid receptors (K-i(kappa) = 6.7 and 5.3 nM, K-i(mu)/K-i(kappa) = 375 and 408, a nd K-i(delta)/K-i(kappa) = 408 and 424, respectively). Since kappa agonists may also cause psychotomimetic effects by interaction with sigma sites, bi nding assays to sigma(1) sites were performed where compounds 15 and 16 sho wed negligible affinity (K-i > 10000). Compounds 15 and 16 were further cha racterized in vivo and showed potent antinociceptive activity in mouse abdo minal constriction tests (ED50 = 0 ss and 1.1 mg/kg, respectively), fully p revented by nor-BNI. Thus, these novel analogues open an exciting avenue fo r the design of peptidomimetics of dynorphin A(1-8).