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Chem. Pharm. Bull. 64(5): 410-419 (2016)

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Chem. Pharm. Bull. 64(5): 410-419 (2016) 410 Chem. Pharm. Bull. 64, 410–419 (2016) Vol. 64, No. 5 Regular Article Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure–Activity Relationship Study of Matrine Alkaloids Hiroyoshi Teramoto, Takayasu Yamauchi,* Yasushi Terado, Sanae Odagiri, Shigeru Sasaki, and Kimio Higashiyama Institute of Medicinal Chemistry, Hoshi University; Ebara, Shinagawa, Tokyo 142–8501, Japan. Received November 30, 2015; accepted February 8, 2016 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 studies for 1 and 2 and their antinociceptive activity using pain relief to cancer patients. Most narcotic analgesics are modifications of the A–D ring systems. The SAR studies µ-opioid receptor (MOR) agonists and have adverse effects showed that the amide group, tertiary amine group, and C- such as addiction,1) respiratory depression,2) and constipa- ring of 1 and 2 were important in determining their activity. tion.3,4) Although stimulation of the κ-opioid receptor (KOR) 4-Dimethylamino-1-pentanoylpiperidine (3) was identified as results in significant analgesia, KOR agonists do not suffer a lead compound through the antinociceptive effect of 1.12–14) from the same adverse effects as MOR agonists. Many KOR We hypothesized that the level of the antinociceptive effect agonists, including ethylketocyclazocine, U-50,488H, and nal- would be affected by the distance between the amide and furafine (TRK-820), have been developed and investigated for amino groups, which are important structural components their analgesic, anti-inflammatory and antipruritic activity5,6) of compound 3. To investigate this, model compounds (4–6) (Fig. 1). However, these agonists suffer from dose-limiting were designed to study the effect of the spatial relationship dysphoria, sedation, and psychotomimetic effects.7,8) Conse- between the amide and amine groups on the agonistic activity quently, the development of a KOR agonist that does not cause (Fig. 2). We also identified that compound 7, 3-Bn analogue of adverse effects is important. compound 3 with a trans-configuration, has antinociceptive We previously reported that (+)-matrine (1) and (+)-allo- effects through KOR which exhibited higher antinociceptive matrine (2), typical matrine-type lupine alkaloids produced by Sophora Leguminosae, have antinociceptive properties identi- cal 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-[35S] thio) trisphosphate ([35S] GTPγS) binding assay with the membranes of spinal cord, indicating that the supraspinal antinociceptive actions induced by 1 and 2 were not caused by direct stimulation of the KOR.11) Although intracerebroventricular pretreatment with an antiserum against dynorphin A (1–17) did not af- fect 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 dynorphiner- gic 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 Fig. 1. Structure of Conventional κ-Opioid Receptor Agonists and agonists, we performed structure–activity relationship (SAR) (+)-Matrine Derivatives * To whom correspondence should be addressed. e-mail: [email protected] © 2016 The Pharmaceutical Society of Japan Vol. 64, No. 5 (2016) Chem. Pharm. Bull. 411 activity than compound 3.15) Because compound 7 exists as a rotamer by amide group, and we anticipated that the anti- nociceptive effects could be different from the rotamers. To investigate this, we designed and synthesized compounds 8 and 9 with the carbonyl group of the amide incorporated into piperidine. A SAR study was carried out to clarify the effect of the positional relationships between the benzyl and car- bonyl group for the rotamers. The antinociceptive effects of the analogues of compound 3 (4–6, 8, 9) were evaluated using acetic acid-induced abdominal contraction tests in mice. Synthesis The synthetic routes for compounds 4a and b–6a and b are shown in Chart 1. Compounds 4a and b were prepared with pentanoyl chloride or benzoyl chloride from 1-methylpi- Fig. 2. Structure of Lead Compound 3 Derivatives Converted Amine peridine (10). The syntheses of 5a and b began with N-ben- and Amide Position zylation of commercially available 4-carboxamidopiperidine Reagents and reaction conditions: (a) RCOCl, DMAP, Et3N, CH2Cl2, 0°C, 94–97%; (b) BnBr, NaHCO3, toluene, reflux, 57%; (c) LiAlH4, Et2O, reflux; (d) HCHO, HCO2H, 100°C, two steps, 83%; (e) Pd(OH)2, H2, EtOH, rt; (f) RCOCl, Et3N, CH2Cl2, rt, two steps, 72–91%; (g) (EtO)2POCH2CN, K2CO3, THF, reflux, 94%; (h) NaBH4, MeOH, Pyridine, reflux, 79%; (i) LiAlH4, THF, 0°C; (j) HCHO, HCO2H, 100°C, two steps, 61%. Chart 1 Reagents and reaction conditions: (a) PhCHO, piperidine, benzene, reflux; (b) Pd–C, H2, MeOH, rt; (c) HCl aq, EtOAc, rt, three steps, 99%; (d) Me2NH, Ti(Oi-Pr)4, THF, reflux, then NaCNBH4, AcOH, rt, 72%; (e) 1-iodopentane, t-BuOK, THF, rt, 74% (dr=2 : 1); (f) t-BuOK, THF, 0°C, 42%. Chart 2 412 Chem. Pharm. Bull. Vol. 64, No. 5 (2016) Reagents and reaction conditions: (a) Me2NH, benzene, reflux, 92%; (b) PtO2, H2, MeOH, rt, 94%; (c) 1-bromopentane, KOH, DMSO, rt, 66%; (d) L-selectride, toluene, −78°C, 99%; (e) DIAD, DPPA, Ph3P, THF, 0°C to rt; (f) Pd–C, H2, HCHO, MeOH, two steps, 69%; (g) 1-iodopentane, t-BuOK, THF, rt, 59%. Chart 3 (11). Amide 12 was converted to the amine by reduction with 16) LiAlH4, and treated with HCHO and HCO2H to yield 13. After debenzylation using Pd(OH)2, acylation of the second- ary amine gave the target compounds 5a and b. Compounds 6a and b were synthesized from 1-benzyl-4-piperidone (14) using the Horner–Wadsworth–Emmons reaction to give olefin 17) 15. Reduction of 15 using NaBH4, followed by reduction of the nitrile and N,N-dimethylation, afforded tertiary amine 18. After debenzylation, acylation of the secondary amine gave the target compounds 6a and b. The synthetic routes for cis- and trans-8a and b are shown in Chart 2. The β-keto lactam 19 was prepared from β-alanine according to an established procedure.18,19) Condensation of 19 with benzaldehyde, followed by hydrogenation with Pd–C and treatment under acidic conditions gave the 3-benzyl derivative (20).20) Reductive amination of 20 using dimethylamine and NaCNBH3 afforded cis-8a as a single diastereomer. Treatment Fig. 3. ORTEP Drawing of cis-9a of cis-8a with potassium tert-butoxide produced the diaste- reomers cis-8b and trans-8b, which could be separated. The tion by Pd(OH)2 in the presence of HCHO, gave (−)-trans-8a. relative configurations of these diastereomers were assigned Compound (−)-trans-8b was obtained by N-pentylation25) be- using coupling constants from 1H-NMR data. The results sug- fore debenzylation. gested that cis-8a could be epimerized to trans-8a under basic Biological Assay The antinociceptive effects of com- conditions. Therefore, epimerization of cis-8a to trans-8a was pounds 4a, b–6a and b, 8a and b, and 9a and b were evaluat- attempted using potassium tert-butoxide. ed in acetic acid-induced abdominal contraction assays (writh- Chart 3 shows the synthetic routes used to prepare cis- and ing tests). The results for 4a and b–6a and b are shown in Fig. trans-9a and b. Ketone 21 was prepared from 19 according 4A. Compared with 3a and b, the effects of 5a and b and 6a an established procedure.19) To prepare cis-9a, enaminone 22 and b were greatly attenuated, while the effects of 4a and b was obtained from ketone 21 and then reduced with PtO2. were similar to those of 3a and b. To investigate if the effects The relative configuration of cis-9a was confirmed by X-ray of 3a and b and 4a and b were mediated through the KOR, crystallography (Fig. 3). To prepare trans-9a and b, ketone 21 we attempted to antagonize these effects by pretreatment with was stereoselectively reduced with L-selectride to yield alcohol the KOR antagonist norbinaltorphimine (norBNI) (Fig. 4B). 23,21) which was submitted to a Mitsunobu reaction using di- Pretreatment with norBNI resulted in a large dampening of phenylphosphoryl azide (DPPA), diisopropyl azodicarboxylate the effect of 3a, but the effect of 4a and b was not dampened. (DIAD), and triphenylphosphine (TPP).22) The prepared cis-9a These results show that the distance between the amide and and trans-9a were converted to cis-9b and trans-9b, respec- amine groups is important for antinociceptive effects through tively, by N-pentylation. the KOR, which is similar effects to what was found for 1 and In order to investigate the antinociception between racemic 2.10) and chiral compounds, (−)-trans-8a and b were synthesized The results for cis- and trans-8a and b, 9a and b are shown by alternative plan as shown in Chart 4.
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