Nonpeptide Analogues of Dynorphin A(1−8):  Design, Synthesis, and Pharmacological Evaluation of κ-Selective Agonists

Abstract

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).

Molecular Hybridization: A Useful Tool in the Design of New Drug Prototypes

“…Among the derivatives of this new series, compounds 139 and 140 stood out due to their high affinities to the naive and cloned κ-opioid receptors, confirming the initial hypothesis that 136 and 137 would be good templates of ligands for this subtype of opioid receptors [50,53].…”

“…The best obtained results were observed for compounds 60 (n = 2) over colon and renal tumor lines (log LC 50 Baraldi and co-workers [29] explored the structures of distamicine-A (64 ) and uramustine (65 , Fig. (9)), a uracil mustard with strong DNA alkylating activity, to synthesize activity >1000 times superior to the distamicine-A (64 ) in the same experimental conditions [29].…”

“…The action of some heterocyclic hydrazone and acylhydrazone derivatives [40,41] in the blood-platelets modulates the arachidonic acid-induced platelet aggregation process, probably due to the inhibition of the isoform 1 of the cyclooxigenase (COX-1) and the consequent reduction of thromboxane A 2 (TXA 2 ) biosynthesis [35]. Pyrazolyl-4-acylhydrazone derivative (96 ) was identified as an TXA 2 inhibitor (IC 50 phenothiazine N-acylhydrazone derivatives 111-116 [35], where the introduction of an acylhydrazone unity in the structural pattern of the neurotrophic phenothiazine scaffold could lead to new neuroactive agents, aiming at the modulation of the COX-3 [43] (Fig. (16 )).…”

“…The safrol (123), an abundant Brazilian natural product, was elected as raw material Opioid analgesics display their activities by means of interaction with three subtypes of receptors: µ, δ and κ [49]. subtype of G protein coupled receptors have been described as therapeutically safer analgesic agents, as they do not present the characteristic morphine side effects which limit its clinical use [50]. Considering that dynorphine A (138) was characterized as the specific endogen ligand of this receptor, structure-activity relationship (SAR) studies between peptidic and non-peptidic ligands of κ receptors led Ronsisvalle and colleagues [51,52] to plan the MPCB (136) and its chlorophenyl analog CCB (137, Fig.…”

“…(19 )) as ligands with high affinity and specificity for κ-opioid receptors. It was believed that the cyclopropyl-methylnormetazocine sub-unity (CPM) would be responsible for the anchoration of the phenolic ring, the basic nitrogen moiety and the additional phenyl ring, in an appropriate conformation for mimicking the recognition of the N-terminal framework of dynorphine A (138) [50].…”