Journal article
ZYKR1, a novel, potent, and peripherally selective kappa opioid receptor agonist reduces visceral pain and pruritus in animal models
European journal of pharmacology, Vol.924, p.174961
06/05/2022
DOI: 10.1016/j.ejphar.2022.174961
PMID: 35443192
Abstract
Opioid receptor agonists are effective analgesic agents. Central activation of the mu and/or kappa opioid receptors (KOR) is associated with CNS side effects, which limits their effectiveness. Recent studies indicated that peripherally restricted, selective KOR agonists were potent analgesics and devoid of CNS-related side effects. To confirm this hypothesis, we designed a novel, potent, and peripherally restricted KOR-selective agonist, ZYKR1. The analgesic efficacy, brain penetration and safety of ZYKR1 were assessed in pre-clinical models. ZYKR1 showed KOR agonistic activity in the cAMP assay, with an EC50 of 0.061 nM and more than 105-fold selectivity over the mu and delta opioid receptors (EC50 > 10 μM). ZYKR1 was not found to bind mu, delta opioid, and NOP receptors in radioligand binding assays. ZYKR1 produced concentration-dependent inhibition of electrically evoked contractions in isolated mouse vas deferens with an IC50 of 1.6 nM ZYKR1 showed peripheral restriction and potent analgesic efficacy in various in-vivo animal models (acetic acid induced visceral pain mouse model, ED50: 0.025 mg/kg, IV; ovariohysterectomy induced postoperative pain rat model, ED50: 0.023 mg/kg, IV; and C48/80 induced pruritus mouse model, ED50: 0.063 mg/kg, IV). In addition, ZYKR1 was devoid of motor coordination, physical dependence, dysphoria, and respiratory depression at 30, 400, 10 and 10-fold of efficacy dose, respectively. In conclusion, ZYKR1 has potent antinociceptive action in visceral pain and pruritus with limited CNS side effects in preclinical models owing to its peripheral restriction.
Details
- Title: Subtitle
- ZYKR1, a novel, potent, and peripherally selective kappa opioid receptor agonist reduces visceral pain and pruritus in animal models
- Creators
- Mukul R. Jain - Cadila HealthcareRakesh B. Patel - Cadila HealthcareKanaiyalal D. Prajapati - Cadila HealthcarePurvi Vyas - Cadila HealthcareDebdutta Bandyopadhyay - Cadila HealthcareVijay Prajapati - Cadila HealthcareRajesh Bahekar - Cadila HealthcarePrakash N. Patel - Cadila HealthcareHarish M. Kawade - Rashtrasant Tukadoji Maharaj Nagpur UniversityDadasaheb M. Kokare - Rashtrasant Tukadoji Maharaj Nagpur UniversityVishwanath Pawar - Cadila HealthcareRanjit Desai - Cadila Healthcare
- Resource Type
- Journal article
- Publication Details
- European journal of pharmacology, Vol.924, p.174961
- DOI
- 10.1016/j.ejphar.2022.174961
- PMID
- 35443192
- ISSN
- 0014-2999
- eISSN
- 1879-0712
- Publisher
- Elsevier B.V
- Language
- English
- Date published
- 06/05/2022
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985132188902771
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