Original endomorphin-1 analogues exhibit good analgesic effects

Y, Wu; Zhao, Xinyi; Gan, Yongan; Zhang, Xuehong; Wei, Hongbin; Wang, Lewei; Liang, Xiaolei; Gao, Xuelin; Liu, Ying; Hu, Junping; Wang, Yiqing

doi:10.1016/j.bmcl.2017.02.034

Cited by 6 publications

(5 citation statements)

References 23 publications

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“…In 2006, the presence of functional MORs, DORs, and KORs in human sperm membranes was reported for the first time [ 7 ]. The effects of exogenous and endogenous opioids on human sperm motility via the three classical opioid receptors have been reported [ 6 , 8 , 14 , 31 ]. In this study, different concentrations of HAGD (10, 1, 0.1, 0.01, 0.001, and 0.0001 µmol/L) did not have a significant negative effect on human sperm motility within the duration of the experiment.…”

Section: Discussionmentioning

confidence: 99%

A Novel Multi-Target Mu/Delta Opioid Receptor Agonist, HAGD, Produced Potent Peripheral Antinociception with Limited Side Effects in Mice and Minimal Impact on Human Sperm Motility In Vitro

Feng²,

Zhang³

et al. 2023

Molecules

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Pain is a common clinical symptom among patients. Although various opioid analgesics have been developed, their side effects hinder their application. This study aimed to develop a novel opioid analgesic, HAGD (H-Tyr-D-AIa-GIy-Phe-NH2), with limited side effects. In vivo studies on mouse models as well as in vitro studies on Chinese hamster ovary (CHO) cells expressing human mu, delta, or kappa opioid receptors (CHOhMOP, CHOhDOP, and CHOhKOP, respectively) and human sperm were conducted. Compared with subcutaneous morphine (10 mg/kg), subcutaneous HAGD (10 mg/kg) produced equipotent or even greater antinociception with a prolonged duration by activating mu/delta opioid receptors in preclinical mouse pain models. The analgesic tolerance, rewarding effects (i.e., conditioned place preference and acute hyperlocomotion), and gastrointestinal transit inhibition of HAGD were significantly reduced compared with those of morphine. Both HAGD and morphine exhibited a withdrawal response and had no impacts on motor coordination. In CHOhMOP and CHOhDOP, HAGD showed specific and efficient intracellular Ca2+ stimulation. HAGD had minimal impact on human sperm motility in vitro, whereas 1 × 10−7 and 1 × 10−8 mol/L of morphine significantly declined sperm motility at 3.5 h. Overall, HAGD may serve as a promising antinociceptive compound.

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Section: Discussionmentioning

confidence: 99%

A Novel Multi-Target Mu/Delta Opioid Receptor Agonist, HAGD, Produced Potent Peripheral Antinociception with Limited Side Effects in Mice and Minimal Impact on Human Sperm Motility In Vitro

Feng²,

Zhang³

et al. 2023

Molecules

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“…In 2006, the presence of functional µ-, δ-, and κ-opioid receptors in human sperm membranes, was reported for the rst time by Agirregoitia and colleagues [16]. Until today, the effects of exogenous and endogenous opioids on human sperm motility by three classical opioid receptors have been studied in lots of literature [15,17,22,23]. In our present study, all the different concentrations of HAGD (10, 1, 0.1 0.01, 0.001 and 0.0001 µMol/L) did not have a signi cant effect on human sperm motility within the duration of the experiment.…”

Section: Discussionmentioning

confidence: 99%

“…HAGD (H-Tyr-D-AIa-GIy-Phe-NH 2 ) was obtained by solution-phase methods with segment-coupling peptide synthesis strategy as our previous reports [22,23]. Morphine hydrochloride was produced by Shenyang First Pharmaceutical Factory (Shenyang, China).…”

Section: Drugs and Preparationsmentioning

confidence: 99%

A Novel Multitarget Mu- and Delta-Opioid Receptors Agonist HAGD Has Peripherally Restrictive Potent Analgesia with Less Side Effects in Mice and Minimal Impact on Human Sperm Motility

Feng

Zhang

et al. 2021

Preprint

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ObjectivePain is a common clinical symptom. Although a variety of opioid analgesics have been developed, the side effects including negative impact on human sperm motility still hinder their application. Aim of this study is to develop a novel opioid analgesic, a multitarget peptide HAGD (H-Tyr-D-AIa-GIy-Phe-NH2) which has less side effects and minimal impact on sperm motility.MethodsThe peripheral antinociceptive effects of HAGD were appraised in a series of preclinical mice pain models, including the tail-flick test, carrageenan-induced inflammatory pain, acetic acid-induced writhing test and formalin test. In conditioned place preference experiment, open field test, gastrointestinal transit test and rotarod test, the side effects of HAGD in mice were assessed. The impacts of HAGD on sperm motility in vitro were investigated.ResultsHAGD produced equipotent antinociception compared with morphine. HAGD was stronger in terms of analgesia intensity in chemical stimulation pain of formalin test phase I. The antinociception was mediated by mu- and delta-opioid receptors. HAGD didn’t induce conditioned place preference and hyperlocomotion, but morphine did. Both HAGD and morphine had no impacts on motor coordination. HAGD had a limited side effect in gastrointestinal transit, while morphine inhibited gastrointestinal transit to a greater extent. However, HAGD had minimal impact on human sperm motility, whereas morphine declined sperm motility at concentrations of 1 × 10-7 mol/l and 1 × 10-8 mol/l at 3.5 h of incubation.Conclusion HAGD may be a better candidate for future development of novel multitarget opioid analgesics with less side effects and minimal impact on human sperm motility.

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“…Furthermore, the guanidino functionality of arginine residues is crucial for the biological activity of many classes of peptides, for example, cell-penetrating peptides (CPPs) − and antimicrobial peptides (AMPs), − the subclasses of which also possess immunomodulatory properties . CPPs facilitate efficient delivery of cargo molecules across cell membranes with potential use in the treatment of bacterial infections − and cancer. , Similarly, guanidinium-rich peptoids have been investigated as molecular transporters in cellular drug delivery. − Guanidinylation may also generate analogues with improved pharmacological properties, for example, guanidinylated aminoglycosides have been shown to exhibit improved RNA-binding affinity that confers increased antibacterial activity. , Additionally, N-terminal guanidinylation of biologically active peptides can lead to increased antimicrobial activity, higher receptor binding affinity, , or prolonged stability in serum and plasma. , …”

Section: Introductionmentioning

confidence: 99%

“…29,30 Additionally, N-terminal guanidinylation of biologically active peptides can lead to increased antimicrobial activity, 31 higher receptor binding affinity, 32,33 or prolonged stability in serum and plasma. 34,35 Efficient guanidinylation protocols for both small molecules and peptides are crucial to facilitate more advanced structure− activity studies, for example, the introduction of guanidino functionalities in peptides or peptidomimetics beyond simple insertion of commercially available guanidine-containing residues during assembly on the solid phase. Rapid synthesis of such compounds is typically complicated by the need to perform a selective cleavage of partially protected intermediates from the resin prior to solution-phase guanidinylation, which is usually followed by another step enabling full deprotection.…”

Section: ■ Introductionmentioning

confidence: 99%

Evaluation of 1H-Triazole-1-[N,N′-Bis(tert-butoxycarbonyl)]carboxamidine in Solution-Phase and On-Resin Guanidinylation

2021

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Several guanidines and guanidinylated peptides have substantial potential as therapeutics, but efficient guanidinylation reagents are vital for easy access to these compounds. Presently, pyrazole-1-carboxamidine type reagents are commonly used in the transformations of amines into corresponding guanidines. Here, we report a comparative study of the utility of 1H-triazole-1-[N,N′-bis(tert-butoxycarbonyl)]carboxamidine, which was synthesized in two steps and readily upscaled to gram amounts. It exhibited excellent performance in solution-phase reactions, rapidly converting a set of representative aliphatic primary and unhindered secondary amines as well as aniline into the corresponding bis(tert-butoxycarbonyl)-protected guanidines. To enable a direct assessment of the reactivity of guanidinylation reagents, conversions were performed in deuterated solvents (d 7-DMF or d 8-THF), allowing for continuous analysis of the reaction mixtures by 1H and 13C NMR. Likewise, 1H-triazole-1-[N,N′-bis(tert-butoxycarbonyl)]carboxamidine proved to be a versatile reagent in solid-phase conversions, for example, a resin-bound test peptide (KFFKFFK) was fully guanidinylated in only 2 h by using 2 equivalents of the reagent per free amino group. Also, 1H-triazole-1-[N,N′-bis(tert-butoxycarbonyl)]carboxamidine proved capable of completely guanidinylating more sterically hindered N-terminal residues (e.g., N-methyl amino acids or a peptoid) in resin-bound peptides. Its superior reactivity and stability demonstrated under heating conditions make 1H-triazole-1-[N,N′-bis(tert-butoxycarbonyl)]carboxamidine a valuable guanidinylation reagent both in solution- and solid-phase synthesis.

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Original endomorphin-1 analogues exhibit good analgesic effects

Cited by 6 publications

References 23 publications

A Novel Multi-Target Mu/Delta Opioid Receptor Agonist, HAGD, Produced Potent Peripheral Antinociception with Limited Side Effects in Mice and Minimal Impact on Human Sperm Motility In Vitro

A Novel Multi-Target Mu/Delta Opioid Receptor Agonist, HAGD, Produced Potent Peripheral Antinociception with Limited Side Effects in Mice and Minimal Impact on Human Sperm Motility In Vitro

A Novel Multitarget Mu- and Delta-Opioid Receptors Agonist HAGD Has Peripherally Restrictive Potent Analgesia with Less Side Effects in Mice and Minimal Impact on Human Sperm Motility

Evaluation of 1H-Triazole-1-[N,N′-Bis(tert-butoxycarbonyl)]carboxamidine in Solution-Phase and On-Resin Guanidinylation

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