Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure–Activity Relationship Study of Matrine Alkaloids

Abstract

The matrine-type alkaloid 4-dimethylamino-1-pentanoylpiperidine (3a) has an antinociceptive effect through its impact on the κ-opioid receptor (KOR). Derivatives of 3a were synthesized by altering its amide and tertiary amine groups, and were evaluated for their antinociceptive effects. The results indicated that the distance between these groups on 3a was optimal for the antinociceptive effect. The effects obtained with compounds 8 and 9 indicated that the relative configuration of the 3-and 4-substituents influenced the effect mediated through the KOR.Key words antinociception; kappa opioid receptor (KOR); matrine; piperidone; acetic acid-induced abdominal contraction test; mouse Narcotic analgesics such as morphine are administered for pain relief to cancer patients. Most narcotic analgesics are µ-opioid receptor (MOR) agonists and have adverse effects such as addiction, 1) respiratory depression, 2) and constipation.3,4) Although stimulation of the κ-opioid receptor (KOR) results in significant analgesia, KOR agonists do not suffer from the same adverse effects as MOR agonists. Many KOR agonists, including ethylketocyclazocine, U-50,488H, and nalfurafine (TRK-820), have been developed and investigated for their analgesic, anti-inflammatory and antipruritic activity 5,6) ( Fig. 1). However, these agonists suffer from dose-limiting dysphoria, sedation, and psychotomimetic effects. 7,8) Consequently, the development of a KOR agonist that does not cause adverse effects is important.We previously reported that (+)-matrine (1) and (+)-allomatrine (2), typical matrine-type lupine alkaloids produced by Sophora Leguminosae, have antinociceptive properties identical to those of pentazocine.9) The effects of 1 were mediated mainly through activation of the KOR and partially through the MOR, and those of 2 were mediated only through the KOR.10) Furthermore, we found that neither 1 nor 2 provided the activation in the guanosine-5′-O-(3-[ 11) Although intracerebroventricular pretreatment with an antiserum against dynorphin A (1-17) did not affect the antinociceptive effect induced by subcutaneous (s.c.) treatment of 1 and 2, the antinociceptive effect was greatly attenuated by intrathecal (i.t.) pretreatment with an antiserum against dynorphin A (1-17) in mice. This suggested that the antinociceptive effect induced by s.c. treatment of 1 and 2 occurred without binding to the KOR in the ventricles of the brain, in where might stimulate the descending dynorphinergic neuron and production of dynorphin in the spinal cord.Because the pharmacological mechanism of action and chemical structures of 1 and 2 differ from conventional KOR agonists, we performed structure-activity relationship (SAR) studies for 1 and 2 and their antinociceptive activity using modifications of the A-D ring systems. The SAR studies showed that the amide group, tertiary amine group, and Cring of 1 and 2 were important in determining their activity. 4-Dimethylamino-1-pentanoylpiperidine (3) was identified as a lead compound through the antinociceptive eff...

Semisynthesis of Matrinic Acid/Alcohol/Ester Derivatives, Their Pesticidal Activities, and Investigation of Mechanisms of Action against Tetranychus cinnabarinus

“…It could be also isolated from the roots of Sophora tonkinensis and Sophora alopecuroides (Kudouzi) . Compound 1 and its derivatives exhibited lots of pharmacological effects such as relieving itching property, stimulating F508del-cystic fibrosis transmembrane conductance regulator activity, anticancer activity, − anti-inflammatory property, antihepatitis B virus activity, − and analgesic activity . On the other hand, it was reported that the compound 1 -based extraction could be used as a botanical pesticide for controlling agricultural pests. , More recently, to improve its pesticidal activities, structural modifications of compound 1 as a lead compound, focused on the C-14 and C-15 positions of its lactam ring, have been conducted in Wang’s and our groups. − Although some derivatives showed promising pesticidal activities, there are still considerable differences in magnitude for activities between them and popular pesticides.…”

Therapeutics for Chemotherapy-Induced Peripheral Neuropathy: Approaches with Natural Compounds from Traditional Eastern Medicine

“…Studies showed that matrine exerted analgesic effects on vincristine-induced pain symptoms via its anti-oxidative, anti-inflammatory, and calcium antagonistic actions [ 85 , 86 ]. Other antinociceptive mechanisms of matrine include κ-opioid receptor agonism [ 184 ] and cholinergic activation in the nervous system [ 185 ]. Recent studies have shown that this substance can be used to reduce the side effects of opioid drugs, such as tolerance and withdrawal symptoms [ 186 , 187 , 188 ].…”

Construction of Multiple Switchable Sensors and Logic Gates Based on Carboxylated Multi-Walled Carbon Nanotubes/Poly(N,N-Diethylacrylamide)

“…However, drug molecules are becoming increasingly popular probes in the field of electrochemistry and medical research, because some drug molecules with electroactivity can be used to investigate the properties of film systems in vitro or used as target drugs to treat diseases in vivo. Matrine and sophoridine are quinolizidine alkaloids isolated from traditional Chinese medicine such as Sophora flavescens, Sophora subprostrata, or Sophora alopecuroides, which are tetracyclic quinolizine compounds with a molecular skeleton and can be regarded as a combination of two quinolizine rings [ 19 , 20 ]. In recent years, it has been discovered that the alkaloids of S. flavescens exhibit anti-arrhythmic, anti-inflammatory, anti-fibrosis, anti-tumor, and numerous other significant pharmacological activities, and various formulations have been widely used in clinical practice [ 21 , 22 , 23 , 24 ].…”