A transition-metal-free synthesis of pyridine derivatives by 6-endo-dig cyclization of N-propargyl enamines was developed. This method is environmentally friendly and is a high atom economy reaction that is easily accessed to provide pyridine derivatives in moderate to good yield by heating N-propargyl enamines in solvent without additives. The total synthesis of onychine was achieved in 51% yield in only two steps by using this method.
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...
A series of new κ opioid receptor (KOR) agonists were developed from the lead compound 4-dimethylamino-1-pentanoylpiperidine (3), a matrine-type alkaloid. Derivatives of 3 were synthesized with a variety of phenyl substituents and evaluated for their antinociceptive effects. Additionally, their selectivity for an opioid receptor was investigated for cis-4c and d, and trans-4g, all of which had high activity exerted through the KOR.Key words antinociceptive effect; kappa opioid receptor; piperidine; matrine; writhing test; mouse We previously reported that (+)-matrine (1) and (+)-allomatrine (2), a typical matrine type lupine alkaloid isolated from some Sophora plants (Leguminosae), have antinociceptive properties identical to those of pentazocine 1) (Fig. 1). The effects of (+)-matrine are mediated mainly through activation of κ opioid receptors (KOR) and partially through μ receptors (MOR), while the effects of (+)-allomatrine are mediated only through activation of KOR.2) Because the skeleton of the matrine type alkaloids differs from those of conventional KOR agonists, such as ethylketocyclazocine, 3) U-50488 4,5) and nalfurafine (TRK-820), 6) they have the potential to be derivatized into novel KOR agonists that may not induce side effects such as dysphoria and psychotomimetic actions 7,8) (Fig. 2). In fact, the structure-activity relationship (SAR) between the antinociceptive effects of these alkaloids and their structures is very interesting. During the development of new KOR agonists, compound 3 was identified as a lead compound by determining the essential structure required for the antinociceptive effects of (+)-matrine.9-11) When compound 3 was derivatized and tested, the antinociceptive effects of 4-dimethylamino-1-pentanoyl-3-phenylpiperidine (4a) were more potent than those of the lead compound 3. On the basis of the Topliss method, 12) we designed and synthesized phenyl derivatives of 4a in an effort to further improve the activity. Herein, we report the synthesis of the derivatives of 4a and their pharmacological effects. SynthesisThe synthetic route to the intermediates, cis-and trans11a-e, is shown in Chart 1. Hydrazones 7a-e were prepared by condensation of commercially available 2,4,6-triisopropylbenzenesulfonyl hydrazide 5 and the respective acetophenones 6a-e. Allylic alcohols 8a-e were obtained through the Shapiro reaction with acrolein.13) Oxidation of 8a-e with MnO 2 yielded the respective dienones, followed by cyclization via a double aza-Michael reaction with benzylamine using microwave irradiation to give piperidones 9a-e.13) Piperidones 9a-e were converted to oximes 10a-e and subsequently reduced with metal sodium in EtOH to yield the separable diastereomers cis-and trans-11a-d, the 3,4-cis (matrine type) and 3,4-trans configuration compounds (allomatrine type). The relative configuration of these diastereomers were assigned by comparison to literature data and using the coupling constants from the 1 H-NMR spectra. 14) Amine 11e, which has a chloro group on the para position of the be...
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