Analogues of (3R)-7-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic). Synthesis and in Vitro and in Vivo Opioid Receptor Antagonist Activity

Runyon, Scott P.; Brieaddy, Lawrence E.; Mascarella, S. Wayne; Thomas, James B.; Navarro, Hernán A.; Howard, James L.; Pollard, Gerald T.; Carroll, F. Ivy

doi:10.1021/jm1004978

Cited by 24 publications

(24 citation statements)

References 45 publications

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“…The recent termination of the phase 1 clinical trials of JDTic due to undisclosed adverse effects (ClinicalTrials.gov, NCT01431586) has further spurred the search for new, safe and shorter acting KOR-selective antagonists. As discussed above, while several new non-peptide KOR antagonists have recently been reported, including some with finite durations of KOR antagonist activity (Runyon et al, 2010;Peters et al, 2011) or with short residence time in the brain (Grimwood et al, 2011;Mitch et al, 2011) after peripheral administration, reports of orally active KOR antagonists have been limited to only four KOR-selective antagonists: JDTic (Beardsley et al, 2005), an analogue of JDTic (Beardsley et al, 2010), an aminobenzyloxyarylamide (Mitch et al, 2011), and a biphenylsulfonamide (Chang et al, 2011). To date, p.o.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, this prolonged duration precludes certain key preclinical studies and could potentially impair clinical development. Recently, several new non-peptide KOR antagonists have been reported (Brugel et al, 2010;Runyon et al, 2010;Grimwood et al, 2011;Mitch et al, 2011;Peters et al, 2011;Frankowski et al, 2012), some of which demonstrated shorter durations of KOR antagonist activity (Runyon et al, 2010;Peters et al, 2011) or were detected for relatively short (<8 h) periods in the brain (Grimwood et al, 2011;Mitch et al, 2011). However, activity after p.o.…”

Section: Introductionmentioning

confidence: 99%

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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

Eans

Ganno

Reilley

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSECyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic k opioid receptor ( CONCLUSIONS AND IMPLICATIONSThe macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood-brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful therapeutics. Abbreviations

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Eans

Ganno

Reilley

et al. 2013

British J Pharmacology

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“…The reaction mixture was bath sonicated for 5 min to obtain a good dispersion, and then stirred at room temperature overnight. Subsequently, 37% hydrochloric acid (HCl, AnalaR grade, BDH) was added drop-wise until the pH value of the solution reached pH 2 [46]. The mixture was stirred for another 12 hours, then filtered on a 0.45 µm PTFE membrane, and washed with water (3 × 30 mL).…”

Section: Methodsmentioning

confidence: 99%

Aqueous cationic, anionic and non-ionic multi-walled carbon nanotubes, functionalised with minimal framework damage, for biomedical application

Chen

Smith

et al. 2014

Biomaterials

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The use of a thermochemical grafting approach provides a versatile means to functionalise as-synthesised, bulk multi-walled carbon nanotubes (MWNTs) without altering their inherent structure. The associated retention of properties is desirable for a wide range of commercial applications, including for drug delivery and medical purposes; it is also pertinent to studies of intrinsic toxicology. A systematic series of water-compatible MWNTs, with diameter around 12 nm have been prepared, to provide structurally-equivalent samples predominantly stabilised by anionic, cationic, or non-ionic groups. The surface charge of MWNTs was controlled by varying the grafting reagents and subsequent post-functionalisation modifications. The degree of grafting was established by thermal analysis (TGA). High resolution transmission electron microscope (HRTEM) and Raman measurements confirmed that the structural framework of the MWNTs was unaffected by the thermochemical treatment, in contrast to a conventional acid-oxidised control which was severely damaged. The effectiveness of the surface modification was demonstrated by significantly improved solubility and stability in both water and cell culture medium, and further quantified by zeta-potential analysis. The grafted MWNTs exhibited relatively low bioreactivity on human immortal alveolar epithelial type 1-like cells (TT1) following 24h exposure as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and lactate dehydrogenase release (LDH) assays. The exposure of TT1 cells to MWNTs suppressed the release of the inflammatory mediators, interleukin 6 (IL-6) and interleukin 8 (IL-8). TEM cell uptake studies indicated efficient cellular entry of MWNTs into TT1 cells, via a range of mechanisms. Cationic MWNTs showed a more substantial interaction with TT1 cell membranes than anionic MWNTs, demonstrating a surface charge effect on cell uptake.

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“…However, the prototypical KOP receptor-selective non-peptide antagonists nor-BNI, 5′-guanidinylnaltrindole (GNTI) and JDTic exhibit exceptionally long activity, antagonizing KOP receptors for weeks after a single dose (Metcalf and Coop, 2005;). This profile could potentially complicate their use as pharmacological tools and as possible therapeutic agents, spurring the search for shorter acting KOP receptor-selective antagonists (Brugel et al, 2010;Runyon et al, 2010;Grimwood et al, 2011;Peters et al, 2011;Frankowski et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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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Analogues of (3R)-7-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic). Synthesis and in Vitro and in Vivo Opioid Receptor Antagonist Activity

Cited by 24 publications

References 45 publications

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

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

Aqueous cationic, anionic and non-ionic multi-walled carbon nanotubes, functionalised with minimal framework damage, for biomedical application

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

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