Nonpeptide analogues of dynorphin A(1-8): design, synthesis, and pharmacological evaluation of kappa-selective agonists.
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).
Ronsisvalle
G
G
Department of Pharmaceutical Sciences, University of Catania, Viale Andrea Doria, 6 - Città Universitaria, 95125 Catania, Italy. ggrmedch@mbox.unict.it
Pasquinucci
L
L
Pittalà
V
V
Marrazzo
A
A
Prezzavento
O
O
Di Toro
R
R
Falcucci
B
B
Spampinato
S
S
D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001392:Azocines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004399:Dynorphins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D010147:Pain Measurement; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D001392:Azocines; D003521:Cyclopropanes; C412817:N-((1-(5-amidinobutylpentylcarbamoyl)-3-methyl-1-butylcarbamoyl)methyl)-1-phenyl-2-((8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methanobenzazocin-3-yl)methyl)cyclopropanecarboxamide; C412818:N-((1-(6-amidinobutylhexylcarbamoyl)-3-methyl-1-butylcarbamoyl)methyl)-1-phenyl-2-((8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methanobenzazocin-3-yl)methyl)cyclopropanecarboxamide; D010446:Peptide Fragments; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D004399:Dynorphins; C026770:dynorphin (1-8)