A Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic in Healthy Male Subjects

This is the first study to be conducted in humans for JDTic, a new chemical entity, with evaluations focusing on the safety, tolerability, and pharmacokinetics (PK) of JDTic following administration of single oral doses. JDTic is a novel, selective κ opioid receptor antagonist and is currently being developed by RTI International as a potential pharmacotherapy to treat cocaine dependence. This study has the possibility of identifying the maximum tolerated dose in humans and a surrogate measure of JDTic pharmacodynamic (PD) activity. Data from this study will be used to plan for and define dose ranges for subsequent studies, as well as to identify potential indicators of JDTic pharmacological activity.

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Research Triangle Institute

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项与 JDTic 相关的文献（医药）

2023-03-01·ACS chemical neuroscience

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-Based Antagonists and Kappa Opioid Receptor

Article

作者: Khan, Md Imdadul H. ; Chittiboyina, Amar G. ; Salahuddin, Mohammed F. ; Worth, Charlie J. ; Akins, Nicholas S. ; Keane, Madeline M. ; Paris, Jason J. ; Mahdi, Fakhri ; Pandey, Pankaj ; Le, Hoang V. ; Kim, Seong Jong ; Doerksen, Robert J. ; Moss, Emaya M.

The kappa opioid receptor (KOR) is involved in the regulation of both the reward and mood processes. Recent reports find that the use of drugs of abuse increases the production of dynorphin and the overall activation of KOR. Long-acting KOR antagonists, such as norbinaltorphimine (nor-BNI), JDTic, and 5'-guanidinonaltrindole (GNTI), have been shown to stop depressive and anxiety-related disorders, which are the common side effects of withdrawal that can lead to a relapse in drug use. Unfortunately, these prototypical KOR antagonists are known to induce selective KOR antagonism that is delayed by hours and extremely prolonged, and their use in humans comes with serious safety concerns because they possess a large window for potential drug-drug interactions. Furthermore, their persistent pharmacodynamic activities can hinder the ability to reverse unanticipated side effects immediately. Herein, we report our studies of the lead selective, salvinorin-based KOR antagonist (1) as well as nor-BNI on C57BL/6N male mice for spontaneous cocaine withdrawal. Assessment of pharmacokinetics showed that 1 is a short-acting compound with an average half-life of 3.75 h across different compartments (brain, spinal cord, liver, and plasma). Both 1 (5 mg/kg) and nor-BNI (5 mg/kg) were shown to reduce spontaneous withdrawal behavior in mice, with 1 producing additional anti-anxiety-like behavior in a light-dark transition test (however, no mood-related effects of 1 or nor-BNI were observed at the current dosing in an elevated plus maze or a tail suspension test). Our results support the study of selective, short-acting KOR antagonists for the treatment of psychostimulant withdrawal and the associated negative mood states that contribute to relapse. Furthermore, we identified pertinent interactions between 1 and KOR via computational studies, including induced-fit docking, mutagenesis, and molecular dynamics simulations, to gain insight into the design of future selective, potent, and short-acting salvinorin-based KOR antagonists.

2022-12-01·Progress in neuro-psychopharmacology & biological psychiatry

PPL-103: A mixed opioid partial agonist with desirable anti-cocaine properties

Article

作者: Cippitelli, Andrea ; Zribi, Gilles ; Toll, Lawrence

Cocaine use disorder (CUD) is a persistent public health problem for which no effective medications are available. PPL-103 is an opioid receptor ligand with partial agonist activity at mu, kappa and delta opioid receptors, with a greater efficacy for kappa and low efficacy at mu receptors. Because chronic cocaine use induces changes in the kappa opioid receptor/dynorphin system, we hypothesized that a kappa partial agonist, such as PPL-103, would attenuate the aversive properties of the upregulated kappa system, resulting in effective treatment approach for CUD. We tested the effects of PPL-103 on cocaine self-administration models that recapitulate core aspects of CUD in humans. We found that PPL-103 reduced both long and short access cocaine self-administration, motivation to respond for cocaine, and binge-like cocaine taking, in rats. Operant responding for food, fentanyl and locomotor behavior were not altered at doses that decreased cocaine infusions. Repeated PPL-103 treatment did not lead to tolerance development. PPL-103 also reduced both priming- and cue-induced reinstatement of cocaine seeking, being more effective in the former. Surprisingly, PPL-103 reduced self-administration parameters and reinstatement in rats previously treated with the long-acting kappa receptor antagonist JDTic more potently than in non-JDTic treated animals, whereas naltrexone injected to rats subsequent to JDTic administration increased self-administration, suggesting that the partial mu agonist activity, rather than kappa agonism is important for reduction in cocaine taking and seeking. However, partial kappa activation seems to increase safety by limiting dysphoria, tolerance and addiction development. PPL-103 displays a desirable profile as a possible CUD pharmacotherapy.

2022-04-20·ACS chemical neuroscience3区 · 医学

Advances in Sulfonamide Kappa Opioid Receptor Antagonists: Structural Refinement and Evaluation of CNS Clearance

3区 · 医学

Article

作者: Brust, Tarsis ; Ma, Huiyong ; Frankowski, Kevin J. ; Lovell, Kimberly M. ; Bohn, Laura M. ; Cameron, Michael D. ; Aubé, Jeffrey

Focused modification of a sulfonamide-based kappa opioid receptor (KOR) antagonist series previously reported by this laboratory was investigated. A total of 32 analogues were prepared to explore linker replacement, constraint manipulation, and aryl group or amine substitution. All analogues were assayed for KOR antagonist activity, and the initial lead compound was assessed for in vivo CNS penetration. The most improved analogue possessed a 4-fold increase of potency (IC₅₀ = 18.9 ± 4.4 nM) compared with the lead compound (IC₅₀ = 83.5 ± 20 nM) from an earlier work. The initial lead compound was found to attain suitable brain levels and to possess a shorter clearance time than canonical KOR antagonists such as JDTic.

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适应症	最高研发状态	国家/地区	公司	日期
可卡因相关疾病	临床1期	美国	Research Triangle Institute	2011-09-09

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


SFN2012	N/A	注意力 corticotropin-releasing factor (CRF) \| kappa-opioid receptor (KOR)	-	JDTic (CRF)	廠構蓋襯顧築蓋夢廠選(齋鹹膚顧衊膚繭襯觸網) = 鏇觸蓋築壓製製製獵鬱蓋艱蓋獵遞鑰夢蓋網範 (觸淵鏇願壓膚獵選鏇築 )	积极	2012-10-16
				JDTic (Vehicle (aCSF))	廠構蓋襯顧築蓋夢廠選(齋鹹膚顧衊膚繭襯觸網) = 鹽構齋艱鹽選網淵獵簾蓋艱蓋獵遞鑰夢蓋網範 (觸淵鏇願壓膚獵選鏇築 )
SFN2006	N/A	-	-	JDTic	憲積壓網淵顧鹽艱鬱顧(網鑰製築網廠鑰選襯選) = shown to be inhibited by JDTic for greater than 45 days 鏇壓醖艱網鹹構顧鏇鏇 (鑰繭蓋願鹽鏇淵積鹽廠 ) 更多	-	2006-10-18
				Placebo