The macrocyclic tetrapeptide [<scp>D</scp>‐<scp>T</scp>rp]<scp>CJ</scp>‐15,208 produces short‐acting κ opioid receptor antagonism in the <scp>CNS</scp> after oral administration

Eans, Shainnel O.; Ganno, Michelle L.; Reilley, Kate J.; Patkar, Kshitij A.; Senadheera, Sanjeewa N.; Aldrich, Jane V.; McLaughlin, Jay P.

doi:10.1111/bph.12132

Cited by 37 publications

(69 citation statements)

References 61 publications

(94 reference statements)

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“…42 The amount of time subjects spent in each of three compartments was measured over a 30 min testing period. Prior to place conditioning, the animals ( n = 89) did not demonstrate significant difierences in their time spent exploring the left (506 ± 14 s) vs right (548 ± 15 s) compartments (p = 0.06; Student’s t-test), resulting in a preconditioning response of –5.0 ± 22 s. During each of the next 2 days, mice were administered vehicle (0.9% saline) and consistently confined in a randomly assigned outer compartment for 40 min, half of each group in the right chamber, half in the left chamber.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior

Váradi

Marrone

Eans

et al. 2015

ACS Chem. Neurosci.

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3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-Hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED50 = 0.33 mg/kg) compared with morphine, mediated through the activation of kappa- and delta-opioid receptors. Despite its kappa agonism, this lead derivative did not cause place aversion or preference in mice in a place-conditioning assay, even at doses 3 times the analgesic ED50. However, pretreatment with the lead compound prevented the reward behavior associated with cocaine in a conditioned place preference assay. Together, these results suggest the promise of dual acting kappa- and delta-opioid receptor agonists as analgesics and treatments for cocaine addiction.

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Section: Methodsmentioning

confidence: 99%

Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior

Váradi

Marrone

Eans

et al. 2015

ACS Chem. Neurosci.

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“…Mice were subjected to 4 days of place conditioning to 0.9% saline and cocaine (10 mg·kg −1 , s.c. in 0.9% saline) as previously described Ross et al, 2012;Eans et al, 2013). The mice were then evaluated for their place preference for 30 min twice weekly over a 3 week period until extinction was established (see Figure 8).…”

Section: Conditioned-place Preference (Cpp) Evaluationmentioning

confidence: 99%

“…or peptide 5 (30 nmol, i.c.v.) on days 28 and 29 2 h prior to a forced swimming session on each day, performed as previously described Ross et al, 2012;Eans et al, 2013). Additional mice were treated for 2 days with vehicle or macrocyclic peptide 5 min, 30 min, 1 h or 2 h prior to an additional session of cocaine conditioning on day 29 ( Figure 8A).…”

Section: Conditioned-place Preference (Cpp) Evaluationmentioning

confidence: 99%

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Alanine analogues of [D‐Trp]CJ‐15,208: novel opioid activity profiles and prevention of drug‐ and stress‐induced reinstatement of cocaine‐seeking behaviour

Aldrich

Senadheera

Ross

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe novel macrocyclic peptide cyclo [Phe-D-Pro-Phe-D-Trp] ([D-Trp]CJ-15,208) exhibits κ opioid (KOP) receptor antagonist activity in both in vitro and in vivo assays. The four alanine analogues of this peptide were synthesized and characterized both in vitro and in vivo to assess the contribution of different amino acid residues to the activity of [D-Trp]CJ-15,208. EXPERIMENTAL APPROACHThe peptides were synthesized by a combination of solid phase peptide synthesis and cyclization in solution. The analogues were evaluated in vitro in receptor binding and functional assays, and in vivo with mice using a tail-withdrawal assay for antinociceptive and opioid antagonist activity. Mice demonstrating extinction of cocaine conditioned-place preference (CPP) were pretreated with selected analogues to evaluate prevention of stress or cocaine-induced reinstatement of CPP. KEY RESULTSThe alanine analogues displayed pharmacological profiles in vivo distinctly different from [D-Trp]CJ-15,208. While the analogues exhibited varying opioid receptor affinities and κ and μ opioid receptor antagonist activity in vitro, they produced potent opioid receptor-mediated antinociception (ED50 = 0.28-4.19 nmol, i.c.v.) in vivo. Three of the analogues also displayed KOP receptor antagonist activity in vivo. Pretreatment with an analogue exhibiting both KOP receptor agonist and antagonist activity in vivo prevented both cocaine-and stress-induced reinstatement of cocaine-seeking behaviour in the CPP assay in a time-dependent manner. CONCLUSIONS AND IMPLICATIONSThese unusual macrocyclic peptides exhibit in vivo opioid activity profiles different from the parent compound and represent novel compounds for potential development as therapeutics for drug abuse and possibly as analgesics. BJP

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“…While this unusual structure confers many desirable drug-like properties -including oral bioavailability and blood-brain barrier permeability [13][14][15] -it makes docking studies and rational design of CJ-15,208 analogs particularly challenging.…”

Section: Introductionmentioning

confidence: 99%

Opioid Ligand Binding to Opioid Receptors: Insight and Implications for Peptide Design

Ferracane¹,

Aldrich²

2015

Peptides 2015, Proceedings of the 24th American Peptide Symposium

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The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration

Cited by 37 publications

References 61 publications

Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior

Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior

Alanine analogues of [D‐Trp]CJ‐15,208: novel opioid activity profiles and prevention of drug‐ and stress‐induced reinstatement of cocaine‐seeking behaviour

Opioid Ligand Binding to Opioid Receptors: Insight and Implications for Peptide Design

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