Nonpeptide analogues of dynorphin A(1-8): design, synthesis, and pharmacological evaluation of kappa-selective agonists
| Autor: | R Di Toro, Barbara Falcucci, Orazio Prezzavento, Valeria Pittalà, Giuseppe Ronsisvalle, Agostino Marrazzo, Santi Spampinato, Lorella Giuseppina Pasquinucci |
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| Rok vydání: | 2000 |
| Předmět: |
Agonist
Cyclopropanes Male Models Molecular medicine.drug_class Stereochemistry Receptors Opioid mu Peptide Chemical synthesis Dynorphins chemistry.chemical_compound Mice Radioligand Assay Structure-Activity Relationship Receptors Opioid delta Drug Discovery medicine Animals Receptor Pain Measurement chemistry.chemical_classification Dipeptide Behavior Animal Receptors Opioid kappa Molecular Mimicry Dynorphin A Psychotomimetic Azocines Peptide Fragments Analgesics Opioid chemistry Opioid Molecular Medicine medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 43(16) |
| ISSN: | 0022-2623 |
| Popis: | Two novel series of kappa opioid receptor agonist analogues of MPCB-GRRI and MPCB-RRI, hybrid ligands of MPCB ((-)-cis-N-(2-phenyl-2-carbomethoxy)cyclopropylmethyl-N-normetazocine ) 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 mu, delta, and kappa opioid receptors were analyzed. Compounds 15 and 16, MPCB-Gly-Leu-NH-(CH(2))(n)()-NH-C(=NH)-C(4)H(9) (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, and K(i)(delta)/K(i)(kappa) = 408 and 424, respectively). Since kappa agonists may also cause psychotomimetic effects by interaction with sigma sites, binding assays to sigma(1) 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 (ED(50) = 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). |
| Databáze: | OpenAIRE |
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