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Synthesis and Nicotinic Activity of Epiboxidine: an Isoxazole Analogue of Epibatidine

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Synthesis and Nicotinic Activity of Epiboxidine: an Isoxazole Analogue of Epibatidine European Journal of Pharmacology 321Ž. 1997 189±194 Synthesis and nicotinic activity of epiboxidine: an isoxazole analogue of epibatidine Barbara Badio, H. Martin Garraffo, Carlton V. Plummer, William L. Padgett, John W. Daly ) Laboratory of Bioorganic Chemistry, National Institute of Diabetes and DigestiÕe and Kidney Diseases, Building 8, Room 1A27, National Institutes of Health, Bethesda, MD 20892, USA Received 22 July 1996; revised 25 October 1996; accepted 29 November 1996 Abstract Synthetic Ž." -epiboxidine Ž exo-2- Ž 3-methyl-5-isoxazolyl . -7-azabicyclowx 2.2.1 heptane. is a methylisoxazole analog of the alkaloid epibatidine, itself a potent nicotinic receptor agonist with antinociceptive activity. Epiboxidine contains a methylisoxazolyl ring replacing the chloropyridinyl ring of epibatidine. Thus, it is also an analog of another nicotinic receptor agonist, ABT 418 ŽŽS .-3-methyl-5- Ž 1- methyl-2-pyrrolidinyl.. isoxazole , in which the pyridinyl ring of nicotine has been replaced by the methylisoxazolyl ring. Epiboxidine was 3 about 10-fold less potent than epibatidine and about 17-fold more potent than ABT 418 in inhibitingw Hx nicotine binding to ab42 nicotinic receptors in rat cerebral cortical membranes. In cultured cells with functional ion flux assays, epiboxidine was nearly equipotent to epibatidine and 200-fold more potent than ABT 418 at ab34Ž5.nicotinic receptors in PC12 cells. Epiboxidine was about 5-fold less potent than epibatidine and about 30-fold more potent than ABT 418 in TE671 cells with abgd11 nicotinic receptors. In a hot-plate antinociceptive assay with mice, epiboxidine was about 10-fold less potent than epibatidine. However, epiboxidine was also much less toxic than epibatidine in mice. Keywords: Epibatidine; Epiboxidine; ABT 418; Nicotinic receptor; Analgesia 1. Introduction methyl-2-pyrrolidinyl.Ž isoxazole Elliott et al., 1995; Gar- vey et al., 1994. , represents a relatively accessible alter- The alkaloid Ž.-epibatidine, isolated from skin of an y ation that could be also applied to epibatidine. ABT 418 Ecuadoran frogŽ. Spande et al., 1992 , has potent antinoci- has been reported to have cognitive enhancing, anxiolytic ceptive activity due to activation of central nicotinic recep- and antinociceptive effects in miceŽ Briggs et al., 1995; torsŽ. Badio and Daly, 1994 . The novel structure of epiba- Brioni et al., 1995; Damaj et al., 1995; Holladay et al., tidine and its marked antinociceptive activity stimulated 1995. The methylisoxazole analog of epibatidine, there- synthetic efforts in many laboratoriesŽ see Szantay et al., Â fore, was synthesized and the nicotinic receptor agonist 1996, for a review of synthesis and pharmacological stud- and antinociceptive activities of the resultant racemate, ies.Ž.Ž. Both - and -epibatidine show selectivity for q y which has been named epiboxidineŽŽ exo-2- 3-methyl-5-iso- central neuronal ab and ganglionic ab nicotinic 42 34Ž5. xazolyl. -7-azabicyclowx 2.2.1 heptane. , were compared to the receptors compared to neuromuscular abgdand central 11 activities of Ž.- and Ž.-epibatidine and of ABT 418, neuronal a receptorsŽ Badio and Daly, 1994; Sullivan et q y 7 itself the S-Ž.-enantioner. Ž." -Epiboxidine proved even al., 1994; Alkondon and Albuquerque, 1995; Decker et al., q more selective than epibatidine for ganglionic nicotinic 1995; Gerzanich et al., 1995. Toxicity is a major consider- receptors, less potent as an antinociceptive agent, and ation for any therapeutic development of epibatidine and it much less toxic. was thought that alterations in the ring systems might provide compounds with better ratios of pharmacological to toxicological activity. The replacement of the pyridinyl 2. Materials and methods ring in nicotine by a methylisoxazolyl ring, as in the nicotinic receptor agonist ABT 418, Ž.S -3-methyl-5- Ž 1- 2.1. Materials Synthetic ABT 418, the S-Ž.q -enantiomer, was gener- ) Corresponding author. Tel.:Ž. 1-301 496-0198; Fax: Ž. 1-301 402-0008. ously provided by Dr. M. DamajŽ Medical College Vir- 0014-2999r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved. PII S0014-2999Ž. 96 00939-9 190 B. Badio et al.rEuropean Journal of Pharmacology 321() 1997 189±194 .Ž.Ž. ginia, Richmond, VA, USA . Synthetic q - and y -epi- NaHCO3 Ž. sat. soln., 10 ml and the mixture extracted with batidine were initially supplied by Drs. Tech-Peng Loh and ethyl acetateŽ. 3=5 ml . The organic layer was dried E.J. CoreyŽ. Harvard University, Cambridge, MA, USA . Ž.anhydrous Na24 SO and the solvent evaporated to yield a Subsequently, Ž.q -epibatidine tartrate Ž levorotatory as free residueŽ. 198 mg consisting of two monobromo derivatives base. was from Research Biochemicals International Ž.60% , a mixture of dibromo derivatives Ž. 20% and start- Ž.Ž.Natick, MA, USA as were y -nicotine ditartrate and ing materialŽ. 20% . A sodium ethoxide solution was pre- 3 mecamylamine.w Hx NicotineŽ. 75.7 Cirmmol was from pared by reaction of sodiumŽ. 55 mg with ethanol Ž. 2 ml New England NuclearŽ. Boston, MA, USA ;22 NaClŽ 0.2 and this solution was added to an ethanolŽ. 6 ml solution mCirml.Ž from Amersham Life Science Arlington Heights, of the crude monobromo derivatives. The reaction mixture IL, USA. ; d-tubocurarine from Boehringer-Mannheim was stirred for 45 min and then H2 O and ethyl acetate Ž.Mannheim, Germany ; carbamylcholine from Sigma Ž St. were added. The organic layer was driedŽ anhydrous Louis, MO, USA. Other compounds were from standard Na24 SO.Ž , the solvent evaporated and a residue 115 mg, commercial sources. estimated yield 24% from tropinone. was obtained. Part of the residueŽ. 54 mg was purified by reverse phase high- 2.2. Synthesis of epiboxidine performance liquid chromatographyŽ. hplc , yielding the ester 4 Ž.12 mg , homogeneous by gc-ms. Acetone oxime The synthetic route to Ž." -epiboxidine Ž.5 originates Ž.3.3 mg was dissolved in tetrahydrofuran Ž. 145 ml and from the commercially available tropinoneŽ Aldrich, Mil- butyllithiumŽ. 1.6 M in hexanes, 200 ml was added. This waukee, WI, USA. and includes a Favorskii rearrangement solution was warmed to 608C for 5 min in a capped tube to contract the tropane ring to the `nortropane' ring found and then, a solution of 4 Ž.10 mg in tetrahydrofuran Ž 60 in epibatidine, followed by reaction of the resultant ester ml. was injected. After stirring at 608C for 45 min, the with the dianion of acetone oxime which after deblocking solvent was evaporated with N2 and concentrated HCl yields Ž." -epiboxidine Ž Fig. 1 . The Favorskii reaction Ž.200 ml was added. This solution was heated in a capped was recently reported in a route to Ž." -epibatidine Ž Xu et tube at 1008C for 3 h. After neutralization with aqueous al., 1996. and the acetone oxime reaction was employed in NaHCO3 Ž. sat. soln., 2 ml extraction with ethyl acetate the synthesis of the nicotine analog ABT 418Ž Elliott et al., Ž.3=2 ml , drying of the organic layer Ž anhydrous Na24 SO . 1995. The details of the synthesis are as follows: and evaporation of the solvent, a residue of Ž." -epiboxi- Tropinone Ž.1, 1 g was dissolved in tetrahydrofuran Ž 10 dine 5 was obtainedŽ. 3.5 mg, 47% from 4 homogeneous ml.Ž. and ethyl chloroformate 5 ml was added. After by gc-ms. Ion-trap ms of 5:mrz 179Ž.Ž. Mq1, 11 , 110 5 , 1 stirring at room temperature overnight, aqueous NaHCO3 82Ž. 9 , 70 Ž 32 . , 69 Ž 100 . , 68 Ž 78 . , 55 Ž. 6 . H-nmrŽ. CDCl3 : Ž.sat. soln., 30 ml was added and the neutral mixture was d5.85Ž.Ž.Ž. s, 1H, H-12 , 3.80 t, 1H, H-5 , 3.75 d, 1H, H-2 , extracted with ethyl acetateŽ. 3=10 ml . The organic layer 3.00Ž. m, 1H , 2.24 Ž s, 3H, CH3 -13 .Ž . Ftir vapor phase . : was driedŽ. anhydrous Na24 SO and the solvent evaporated 2979Ž 100 . , 2884 Ž. 24 , 1599 Ž. 46 , 1422 Ž. 42 , 1368 Ž. 12 , to yield a residue of tropinone carbamate Ž.2, 1.01 g, 71% 1221Ž. 9 , 1048 Ž. 9 , 1009 Ž. 12 , 912 Ž. 34 , 790 Ž. 34 cmy1 . homogeneous by gas chromatography-mass spectrometry Ž.gc-ms . Tropinone carbamate Ž2, 169 mg . was dissolved 2.3. Ion flux assays with cultured cells in CH22 ClŽ. 600 ml and a solution of bromine Ž. 50 mlin 30% HBr in acetic acidŽ. 550 ml was added with stirring. Rat pheochromocytoma PC12 cells were provided by After 45 min, the solution was neutralized with aqueous Dr. G. GuroffŽ. NIH, Bethesda, MD, USA . Human medul- Fig. 1. Synthetic route to Ž." -epiboxidine. B. Badio et al.rEuropean Journal of Pharmacology 321() 1997 189±194 191 loblastoma TE671 cells were from the American Type recentrifugation in ice-cold Tris buffer. The final pellet Culture CollectionŽ. Rockville, MD, USA . The PC12 cells was resuspended in ice-cold Tris buffer and stored at were grown in Dulbecco's modified Eagle medium with y708C until needed. Aliquots were diluted to a concentra- 6% fetal calf serum, 6% horse serum and penicillinŽ 100 tion of 1±5 mgrml for binding assays. Protein concentra- Urml.Ž. and streptomycin 100 mgrml . The TE671 cells tions were determined by the bicinchoninic acid protein were grown in Dulbecco's modified Eagle medium with assayŽ. Pierce Chemical Co., Rockford, IL, USA , using 3 10% fetal calf serum and penicillinŽ. 100 Urml and bovine albumin as a standard.w Hx Nicotine receptor bind- streptomycinŽ. 100 mgrml . Cells were grown at 378Cin ing was assayed as described previouslyŽ Badio and Daly, an atmosphere enriched in CO2 . 1994.Ž. in 20 mM HEPES buffer pH 7.4 , containing 1 mM Stimulation of sodium-22 influx was assayed in cul- MgCl22 , 120 mM NaCl, 5 mM KCl and 2 mM CaCl .
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