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ABSTRACT
Introduction
The diverse neuro- and immunomodulatory effects of kynurenine pathway (KP) enzymes and metabolites exert offer possibilities for intervention in diseases such as autoimmunity, neurodegeneration, and neoplastic processes.
Areas covered
This review focuses on data obtained from the preclinical and clinical use of a KP metabolite analog and structurally related compounds. 4-Cl-KYN has completed clinical trials in depression without success. However, the good safety data give hope for further trials in suicide prevention, neuropathic pain, and dyskinesia. Quinoline-3-carboxamide derivatives laquinimod, paquinimod, and tasquinimod show structural similarities to kynurenines. Laquinimod and paquinimod show promising results in the treatment of autoimmune diseases, tasquinimod is considered primarily as an anti-cancer drug. Data available until 31 May 2020 at Clinicaltrials.gov and PubMed have been reviewed.
Expert opinion
The failure of 4-Cl-KYN for use as an anti-depressant may be related to inadequate concentration, or that the ketamine-like rapid anti-depressant effect is not produced via NMDAR modulation. Further clarification may emerge from studies involving higher drug concentration, and/or from identification of ketamine targets. Clinical application trials in very diverse indications of structurally related quinoline-3-carboxamides and the wide range of their mode of action warrant further studies permitting direct comparison of effects and better target identification.
Abbreviations
| 3-HK: | = | 3-hydroxy-kynurenine |
| 4-Cl-KYN: | = | 4-Chlorokynurenine |
| 7-Cl-KYN: | = | 7-chlorokynurenic acid |
| AA: | = | anthranilic acid |
| AD: | = | Alzheimer’s disease |
| AHR: | = | Aryl Hydrocarbon Receptor |
| ALP: | = | alkaline phosphatase |
| ALS: | = | amyotrophic lateral sclerosis |
| ALT: | = | alanine aminostransferase |
| AMD: | = | age-related macular degeneration |
| AMPA: | = | α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid |
| ASSR: | = | Auditory Steady State Response |
| BBB: | = | blood-brain barrier |
| BDNF: | = | brain-derived neurotrophic factor |
| CD: | = | Crohn’s disease |
| CNS: | = | central nervous system |
| CRP: | = | C reactive protein |
| CRPC: | = | castration-resistant prostate cancer |
| CSF: | = | cerebrospinal fluid |
| DDI: | = | drug-drug interaction |
| DSS: | = | dextran sulfate sodium |
| EAE: | = | experimental autoimmune encephalomyelitis |
| fMRI: | = | functional magnetic resonance imaging |
| GABA: | = | Gamma Amino Butyric Acid |
| GLAST: | = | glutamate-aspartate transporter |
| GluT: | = | glutamate transporter |
| GPR35: | = | G-protein coupled receptor 35 |
| HAA: | = | hydroxyanthranilic acid |
| HD: | = | Huntington’s disease |
| HDAC: | = | histone deacetylase |
| H-PGDS: | = | hematopoietic prostaglandin D synthase |
| IDO: | = | indoleamine-2,3-dioxygenase |
| KAT: | = | kynurenine aminotransferase |
| KMO: | = | kynurenine-3-monooxygenase |
| KP: | = | kynurenine pathway |
| KYNA: | = | kynurenic acid |
| KYNU: | = | kynureninase |
| LAQ: | = | laquinimod |
| LDH: | = | lactate dehydrogenase |
| LID: | = | levodopa induced dyskinesia |
| L-KYN: | = | L-kynurenine |
| LPS: | = | lipopolysaccharide |
| MADRS: | = | Montgomery and Asberg Depression Rating Scale |
| MDD: | = | major depressive disorder |
| MDSCs: | = | myeloid-derived suppressor cells |
| mI: | = | Myo-inositol |
| MMF: | = | mycophenolate mofetil |
| MoA: | = | mode of action |
| MRP14: | = | migration inhibitory factor-related protein 14 |
| MRS: | = | 1H-magnetic resonance spectroscopy |
| MS: | = | multiple sclerosis |
| NMDAR: | = | N-methyl-D-aspartate receptor |
| NOD: | = | non-obese diabetic |
| PAQ: | = | paquinimod |
| PBVC: | = | percent brain volume change |
| PD: | = | Parkinson’s disease |
| PFS: | = | progression free survival |
| PPMS: | = | primary progressive multiple sclerosis |
| PSA: | = | prostate-specific antigen |
| Q-Motor: | = | Quantitative Motor |
| QUIN: | = | Quinolinic acid |
| RAGE: | = | receptor for advanced glycation end products |
| RRMS: | = | relapsing remitting multiple sclerosis |
| SLE: | = | systemic lupus erythematosus |
| SNRI: | = | serotonin–norepinephrine reuptake inhibitor |
| SSc: | = | systemic sclerosis |
| SSRI: | = | selective serotonin reuptake inhibitor |
| TASQ: | = | tasquinimod |
| TDO: | = | tryptophan-2,3-dioxygenase |
| TLR4: | = | Toll-like receptor 4 |
| TPGS: | = | D-α-Tocopherol polyethylene glycol 1000 succinate |
| Trp: | = | Tryptophan |
| Tsk-1: | = | tight skin 1 |
| UHDRS: | = | Unified Huntington’s Disease Rating Scale |
| α7nAChR: | = | α7 nicotinic acetylcholine receptor |
Article highlights
• The kynurenine pathway offers possibilities of reaching both neuro- and immunomodulatory effects. We give a short overview of the main targets of kynurenine pathway metabolites.
• 4-Cl-KYN, a halogenated analog of kynurenine has been proven to be safe in clinical trials, but ineffective as a rapid-acting anti-depressant. Combined used with probenecid might improve effectivity, and trials are ongoing for suicide prevention, neuropathic pain relief, and Parkinson’s disease-related dyskinesia.
• Two out of three quinoline-3-carboxamides discussed here, laquinimod and paquinimod have been assayed in clinical trials for autoimmune diseases based on their immunomodulatory effects presumed via S100A9 protein interaction and/or AHR activation.
• Laquinimod has been proven to be effective in clinical trials of multiple sclerosis, Crohn’s disease and lupus nephritis.
• Paquinimod showed beneficial effects on alleviating systemic sclerosis symptoms.
• A third related quinoline-3-carboxamide, tasquinimod has been used primarily as an anti-cancer compound based on its anti-angiogenic and immunomodulatory activity, however, diverse adverse events and lack of effect on patient survival led to the termination of clinical trials.
• Several questions concerning the effective use of these drugs await further clarification. Among these, we emphasize the need for better target identification with respect to receptor subunits, localization and ligand specificity, and systemic comparisons of the effects of structurally related quinoline-3-carboxamide compounds. Advanced techniques of gene manipulation offer possibilities to construct dedicated models for these.
This box summarizes the key points contained in the article.
Acknowledgments
We would like to thank Katalin Boros M.D. (Manchester, United Kingdom) for the help in English language editing.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.