Efecto del compuesto N-2,6-dicloro-aralquil- 2-Aminoindano en la conducta estereotipada de ratas. Acción dopaminérgica selectiva central sobre los ganglios basales más que en las estructuras límbicas.
Effect of the compound N-2,6-dichloro-aralkyl-2-aminoindane on the stereotyped behavior of rats. Selective action on the central dopaminergic system in the basal ganglia over limbic structures.
Palabras clave:
profármaco, enfermedad de Parkinson, enfermedades neurodegenerativas
Resumen
La dopamina 1, está implicada en trastornos neurodegenerativos que afectan al sistema nervioso central (SNC) tales como la enfermedad de Parkinson, entre otros. Aunque no se dispone aún de ningún fármaco capaz de prevenir, detener o curar la progresión de estas enfermedades, son numerosos los compuestos que han sido diseñados, sintetizados y evaluados farmacológicamente, que han aportado las generalizaciones farmacofóricas del receptor dopaminérgico, necesarias para la búsqueda de un fármaco capaz de mejorar o curar estas patologías. Los derivados 2-aminoindano-N-aralquílicos han mostrado tener actividad selectiva en el sistema dopaminérgico central, de modo tal que los compuestos clorhidratos de N-[(2,4-diclorofenil)-1-metil-etil]-2-aminoindano 2 y N-[(3,4-diclorofenil)-1-metil-etil]-2-aminoindano 3 demostraron tener actividad agonística mediada por mecanismos dopaminérgicos centrales. Con el propósito de contribuir en la búsqueda de nuevos fármacos que permitan restablecer la homeostasis de la transmisión dopaminérgica en la enfermedad de Parkinson, el compuesto N-2,6-dicloro-aralquil-2-aminoindano 4 fue diseñado a través de estrategias de la química medicinal, que contienen las aproximaciones farmacofóricas de los profármacos. La evaluación farmacológica del compuesto 4, en la conducta estereotipada en ratas macho de la cepa Sprague Dawley, demostró tener actividad agonística a través de la activación de los mecanismos dopaminérgicos centrales y mostró mayor selectividad en las respuestas de conductas estereotipadas propias de los ganglios basales sobre las respuestas conductuales propias de las estructuras límbicas.
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Brichta L, Greengard P, Flajolet M. Advances in the pharmacological treatment of Parkinson’s disease: targeting neuro-transmitter systems. Trends Neurosci 2013; 36(9): 543-554. https://doi.org/10.1016/j. tins.2013.06.003
Aono M, Iga J, Ueno S, Agawa M, Tsuda T, Ohmori T. Neuropsychological and psychiatric assessments following bilateral deep brain simulation of the subthalamic nucleus in Japanese patients with Parkinson’s disease. J Clin Neurosci 2014; 21(9): 1595-1598. https://doi.org/10.1016/j.jocn.2013.12.020
Zhang C, Han Q, Chen N, Yuan Y. Research on developing drugs for Parkinson’s disease. Brain Res Bull 2021; 168: 100-109. https://doi.org/10.1016/j.brainres- bull.2020.12.017
Krishnan S, Pisharady KK. Surgical treatment of levodopa-induced dyskinesia in parkinson’s disease. Ann Indian Acad Neurol 2017 [citado, 2022 septiembre 15] Disponible en: https://doi.org/10.4103/ aian.AIAN_244_17.
Munhoz RP, Cerasa A, Okun MS. Surgical treatment of dyskinesia in Parkinson´s disease. Front Neurol 2014 [citado, 2022 septiembre 15] Disponible en: https://doi. org/10.3389/fneur.2014.00065.
Zhang A, Neumeyer J, Baldessarini R. Recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders. Chem Rev 2007; 107(1): 274-302. https://doi.org/10.1021/cr050263h
Ross C, Margolis R. Neurogenetics: insights into degenerative diseases and approaches to schizophrenia. Clin Neurosci Res 2005; 5(1): 3-14. https://doi.org/10.1016/j.cnr.2005.07.001
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Park H, Urs A, Zimmerman J, Liu C, Wang Q, Urs N. Structure-functional- selectivity relationship studies of novel apomorphine analogs to develop D1R/D2R biased ligands. ACS Med Chem Lett 2020; 11(3): 385−392. https://doi.org/10.1021/ acsmedchemlett.9b00575
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Rodríguez L, Medina Y, Suárez H, Migliore B, Israel A, Charris J, López S, Caldera J, Angel J. Conformational theoretical study of substituted and non-substituted N-aralkyl-2-aminoindans and its relation with dopaminergic activity. J Mol Struct THEOCHEM 2003; 636(1-3): 1-8. https:// doi.org/10.1016/S0166-1280(03)00023-X.
Angel J, Charris J, Israel A, Migliore B, Suárez H, Garrido M, López S, Díaz E, Fer-Velásquez y coler R, Michelena E, Rodríguez L, Silva J, Moronta A, Espinoza G, Quintero L. Perfil dopaminérgico del compuesto 2-aminoin- dano-N-aralquil sustituido. Arch Venezol Terap Farmacol 2004; 23(2): 136-142.
Andujar S, Garibotto F, Migliore B, Angel J, Charris J, Enriz R. Molecular recognition and binding mechanism of N-aralkyl substituted 2-aminoindans to the dopamine D2 receptor. A theoretical study. J Argent Chem Soc 2006; 94: 1-11.
Angel J. Una compilación en el diseño y evaluación farmacológica preliminar de nuevos compuestos con actividad dopaminérgica central. Invest Clin 2008; 49(1): 71-73.
Andujar S, Migliore B, Charris J, Israel A, Suárez H, López S, Garrido M, Cabrera E, Visbal G, Rosales C, Suvire F, Enriz R, Angel J. Synthesis, dopaminergic profile and molecular dynamics calculations of N- Aralkyl substituted 2-aminoindans. Bioorg Med Chem 2008; 16(6): 3233-3244. https:// doi.org/10.1016/j.bmc.2007.12.027
Ferrer R, Urdaneta N, Porta N, Rodríguez L, Rosales C, Espinoza G, Angel L, Balza K, Perdomo L, Faría A, Dabian A, Zapata M, Linero A, Acurero G, Israel A, Garrido M, Suárez H, Migliore B, López S, Charris J, Ramírez M, Angel J. Novedosos agentes dopaminérgicos centrales derivados del 2-aminoindano-4,7disustituido atípico. Síntesis y perfil farmacológico central. Invest Clin 2015; 56(2): 137-154.
Perdomo L, Balza K, Acurero G, Angel L, Dabian A, Faría A, Linero A, Zapata M, Vera M, Migliore, Suárez H, Israel A, Charris J, López S, Ramírez M, Angel J. Design, synthesis and preliminary pharma- cologic evaluation of 2-aminoindane-quino- line analogues as dopaminergic agents. Der Pharma Chem 2015; 7(5): 130-135.
Montero L, Velasquez M, Caldera J, Vera M, Blanco C, Angel L, Migliore B, Charris J, Israel A, López S, Izquierdo R, Ortega J, Ramírez M, Angel J. Síntesis y evaluación farmacológica de los novedosos agentes dopaminérgicos centrales análogos del N-dicloroaralquil-2-aminoindano. Rev Fac Farm 2018; 81(1-2): 41-50.
Castall B, Marsden CD, Naylor RJ, Pycock CJ. Stereotyped behavior patterns and hyperactivity induced by amphetamine and apomorphine after discrete 6-hydroxydopa-mine lesions of extrapyramidal and meso-limbic nuclei. Brain Res 1977; 123(1): 89-111. https://doi.org/10.1016/0006-8993 (77)90645-X.
Snedecord G, Cochnar W. Statistical Methods. 7th Ed USA: Iowa State University Press Ames; 1982.
Costall B, Naylor RJ, Cannon JG, Lee TJ. Differentiation of the dopamine mechanisms mediating stereotyped behavior and hyperactivity in the nucleus accumbens and caudate-putamen. J Pharm Pharmacol 1977; 29(1): 337-342. https://doi. org/10.1111/j.2042-7158.1977.tb11331.x
Creese L, Iversen SD. The pharmacological and anatomical substrates of the amphetamine response in the rat. Brain Res 1975; 83(3): 419-436. https://doi. org/10.1016/0006-8993(75)90834-3
Chartoff EH, Marck BT, Matsumoto AM, Dorsa DM, Palmiter RD. Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation. Proc Natl Acad Sci USA 2001; 98(18): 10451-10456. https://doi.org/10.1073/pnas.181356498 Israel A, Torres M, Cierco M, Barbella
Y. Further evidence for a dopaminergic involvement in the renal action of centrally administered atrial natriuretic peptide in rats. Brain Res Bull 1991; 27(5): 739-742. https://doi.org/10.1016/0361-9230(91)90056-P
Orfila L, Angel J, Torres M, Barbella Y, Israel Evidence for a dopaminergic involvement in the renal action of centrally administered JA116a, a novel compound with possible dopaminergic activity in rats. J Pharm Pharmacol 1994; 46(5): 397-399. https://doi. org/10.1111/j.2042-7158.1994.tb03825.x
Seeger TF, Seymour PA, Schmidt AW, Zorn SH, Schulz DW, Lebel LA, McLean S, Gua- nowsky V, Howard HR, Lowe JA. Ziprasidone (CP-88,059): A new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharmacol Exp Ther 1995; 275(1): 101-113.
Murphy S, Owen R, Tyrer P. Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks treatment with diazepam or buspirone. Br J Psychia-Investigación Clínica 64(1): 2023
Estudio conductual estereotipado del compuesto N-2,6-dicloro-aralquil-2-Aminoindano 27t ry 1989; 154(4): 529-534. https://doi. org/10.1192/bjp.154.4.529.
Angel J, Santiago A, Rossi R, Migliore B, Barolo S, Andujar S, Hernández V, Rosales C, Charris J E, Suarez H, Israel A, Ramírez MM, Ortega J, Herrera Cano N, Enriz RD. Synthesis and preliminary pharmacological evaluation of methoxilated indoles with possible dopaminergic central action. Lat Am J Pharm 2011; 30(10): 1934-1942.
Angel LB, Balza K, Perdomo LE, Dabian AS, Faría AR, Linero AR, Migliore B, Suárez H, Charris J, Israel A, Ramírez MM, Angel JE. Síntesis y evaluación farmacológica preliminar de nuevos compuestos quinolínicos con actividad anti Corea de Huntington. Rev Fac Farm 2015; 78(1-2):94-100.
Lucas G, De Deurwaerdère P, Caccia S, Spampinato U. The effect of serotonergic agents on haloperidol-induced striatal dopamine release in vivo: opposite role of Jeon BS, Jackson-Lewis SV, Burke RE. 6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration 1995; 4(2): 131-137. https://doi.org/10.1006/ neur.1995.0016
Ungerstedt U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 1968; 5(1): 107-110. https://doi.org/10.1016/0014-2999(68)90164-7
Meltzer HY. Serotonergic mechanisms as targets for existing and novel antipsychotics. Handb Exp Pharmacol 2012; 212: 87-124. https://doi.org/10.1007/978-3-642-25761-2_4
Ushijima I, Carino M, Horita A. Involvement of D1 and D2 dopamine systems in the behavioral effects of cocaine in rats. Pharmacol Biochem Behav 1995; 52(4):737-741. https://doi.org/10.1016/0091-3057(95)00167-U.5-HT and 5-HT
Simola N, Morelli M, Carta AR. The 6-hy- droxydopamine model of Parkinson’s disease. Neurotox Res 2007; 11(3-4): 151-167. https://doi.org/10.1007/BF03033565.
Thoenen H, Tranzer JP. Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-Hydroxydopamine. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 1968; 261(3): 271-288. https://doi.org/10.1007/BF00536990. Psychopharmacology 1984; 82(4): 409-410. https://doi.org/10.1007/BF00427697.
Nichols DE. The development of novel dopamine agonists. ACS Symp Ser Am Chem Soc 1983; 224(9): 201-221. https://doi. org/10.1021/bk-1983-0224.ch009.
Beaulieu J, Gainetdinov R. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 92011; 63(1): 182-217. https://doi.org/10.1124/ pr.110.002642
Brichta L, Greengard P, Flajolet M. Advances in the pharmacological treatment of Parkinson’s disease: targeting neuro-transmitter systems. Trends Neurosci 2013; 36(9): 543-554. https://doi.org/10.1016/j. tins.2013.06.003
Aono M, Iga J, Ueno S, Agawa M, Tsuda T, Ohmori T. Neuropsychological and psychiatric assessments following bilateral deep brain simulation of the subthalamic nucleus in Japanese patients with Parkinson’s disease. J Clin Neurosci 2014; 21(9): 1595-1598. https://doi.org/10.1016/j.jocn.2013.12.020
Zhang C, Han Q, Chen N, Yuan Y. Research on developing drugs for Parkinson’s disease. Brain Res Bull 2021; 168: 100-109. https://doi.org/10.1016/j.brainres- bull.2020.12.017
Krishnan S, Pisharady KK. Surgical treatment of levodopa-induced dyskinesia in parkinson’s disease. Ann Indian Acad Neurol 2017 [citado, 2022 septiembre 15] Disponible en: https://doi.org/10.4103/ aian.AIAN_244_17.
Munhoz RP, Cerasa A, Okun MS. Surgical treatment of dyskinesia in Parkinson´s disease. Front Neurol 2014 [citado, 2022 septiembre 15] Disponible en: https://doi. org/10.3389/fneur.2014.00065.
Zhang A, Neumeyer J, Baldessarini R. Recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders. Chem Rev 2007; 107(1): 274-302. https://doi.org/10.1021/cr050263h
Ross C, Margolis R. Neurogenetics: insights into degenerative diseases and approaches to schizophrenia. Clin Neurosci Res 2005; 5(1): 3-14. https://doi.org/10.1016/j.cnr.2005.07.001
Del’guidice T, Lemasson M, Beaulieu JM. Role of beta-arrestin 2 downstream of dopamine receptors in the basal ganglia. Front Neuroanat 2011 [citado, 2022 septiembre 15] Disponible en: https://doi. org/10.3389/fnana.2011.00058.
Park H, Urs A, Zimmerman J, Liu C, Wang Q, Urs N. Structure-functional- selectivity relationship studies of novel apomorphine analogs to develop D1R/D2R biased ligands. ACS Med Chem Lett 2020; 11(3): 385−392. https://doi.org/10.1021/ acsmedchemlett.9b00575
Charris J, Perez J, Dominguez J, Angel J, Duerto J, Salazar M, Acosta H. N-aralkyl substitution of 2-aminoindans. Synthesis and their inotropic and chronotropic activity in isolated guinea pig atria. Chem Inform Abstr 1998; 29(14): 0-0. https://doi. org/10.1002/chin.199814095.
Rodríguez L, Medina Y, Suárez H, Migliore B, Israel A, Charris J, López S, Caldera J, Angel J. Conformational theoretical study of substituted and non-substituted N-aralkyl-2-aminoindans and its relation with dopaminergic activity. J Mol Struct THEOCHEM 2003; 636(1-3): 1-8. https:// doi.org/10.1016/S0166-1280(03)00023-X.
Angel J, Charris J, Israel A, Migliore B, Suárez H, Garrido M, López S, Díaz E, Fer-Velásquez y coler R, Michelena E, Rodríguez L, Silva J, Moronta A, Espinoza G, Quintero L. Perfil dopaminérgico del compuesto 2-aminoin- dano-N-aralquil sustituido. Arch Venezol Terap Farmacol 2004; 23(2): 136-142.
Andujar S, Garibotto F, Migliore B, Angel J, Charris J, Enriz R. Molecular recognition and binding mechanism of N-aralkyl substituted 2-aminoindans to the dopamine D2 receptor. A theoretical study. J Argent Chem Soc 2006; 94: 1-11.
Angel J. Una compilación en el diseño y evaluación farmacológica preliminar de nuevos compuestos con actividad dopaminérgica central. Invest Clin 2008; 49(1): 71-73.
Andujar S, Migliore B, Charris J, Israel A, Suárez H, López S, Garrido M, Cabrera E, Visbal G, Rosales C, Suvire F, Enriz R, Angel J. Synthesis, dopaminergic profile and molecular dynamics calculations of N- Aralkyl substituted 2-aminoindans. Bioorg Med Chem 2008; 16(6): 3233-3244. https:// doi.org/10.1016/j.bmc.2007.12.027
Ferrer R, Urdaneta N, Porta N, Rodríguez L, Rosales C, Espinoza G, Angel L, Balza K, Perdomo L, Faría A, Dabian A, Zapata M, Linero A, Acurero G, Israel A, Garrido M, Suárez H, Migliore B, López S, Charris J, Ramírez M, Angel J. Novedosos agentes dopaminérgicos centrales derivados del 2-aminoindano-4,7disustituido atípico. Síntesis y perfil farmacológico central. Invest Clin 2015; 56(2): 137-154.
Perdomo L, Balza K, Acurero G, Angel L, Dabian A, Faría A, Linero A, Zapata M, Vera M, Migliore, Suárez H, Israel A, Charris J, López S, Ramírez M, Angel J. Design, synthesis and preliminary pharma- cologic evaluation of 2-aminoindane-quino- line analogues as dopaminergic agents. Der Pharma Chem 2015; 7(5): 130-135.
Montero L, Velasquez M, Caldera J, Vera M, Blanco C, Angel L, Migliore B, Charris J, Israel A, López S, Izquierdo R, Ortega J, Ramírez M, Angel J. Síntesis y evaluación farmacológica de los novedosos agentes dopaminérgicos centrales análogos del N-dicloroaralquil-2-aminoindano. Rev Fac Farm 2018; 81(1-2): 41-50.
Castall B, Marsden CD, Naylor RJ, Pycock CJ. Stereotyped behavior patterns and hyperactivity induced by amphetamine and apomorphine after discrete 6-hydroxydopa-mine lesions of extrapyramidal and meso-limbic nuclei. Brain Res 1977; 123(1): 89-111. https://doi.org/10.1016/0006-8993 (77)90645-X.
Snedecord G, Cochnar W. Statistical Methods. 7th Ed USA: Iowa State University Press Ames; 1982.
Costall B, Naylor RJ, Cannon JG, Lee TJ. Differentiation of the dopamine mechanisms mediating stereotyped behavior and hyperactivity in the nucleus accumbens and caudate-putamen. J Pharm Pharmacol 1977; 29(1): 337-342. https://doi. org/10.1111/j.2042-7158.1977.tb11331.x
Creese L, Iversen SD. The pharmacological and anatomical substrates of the amphetamine response in the rat. Brain Res 1975; 83(3): 419-436. https://doi. org/10.1016/0006-8993(75)90834-3
Chartoff EH, Marck BT, Matsumoto AM, Dorsa DM, Palmiter RD. Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation. Proc Natl Acad Sci USA 2001; 98(18): 10451-10456. https://doi.org/10.1073/pnas.181356498 Israel A, Torres M, Cierco M, Barbella
Y. Further evidence for a dopaminergic involvement in the renal action of centrally administered atrial natriuretic peptide in rats. Brain Res Bull 1991; 27(5): 739-742. https://doi.org/10.1016/0361-9230(91)90056-P
Orfila L, Angel J, Torres M, Barbella Y, Israel Evidence for a dopaminergic involvement in the renal action of centrally administered JA116a, a novel compound with possible dopaminergic activity in rats. J Pharm Pharmacol 1994; 46(5): 397-399. https://doi. org/10.1111/j.2042-7158.1994.tb03825.x
Seeger TF, Seymour PA, Schmidt AW, Zorn SH, Schulz DW, Lebel LA, McLean S, Gua- nowsky V, Howard HR, Lowe JA. Ziprasidone (CP-88,059): A new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharmacol Exp Ther 1995; 275(1): 101-113.
Murphy S, Owen R, Tyrer P. Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks treatment with diazepam or buspirone. Br J Psychia-Investigación Clínica 64(1): 2023
Estudio conductual estereotipado del compuesto N-2,6-dicloro-aralquil-2-Aminoindano 27t ry 1989; 154(4): 529-534. https://doi. org/10.1192/bjp.154.4.529.
Angel J, Santiago A, Rossi R, Migliore B, Barolo S, Andujar S, Hernández V, Rosales C, Charris J E, Suarez H, Israel A, Ramírez MM, Ortega J, Herrera Cano N, Enriz RD. Synthesis and preliminary pharmacological evaluation of methoxilated indoles with possible dopaminergic central action. Lat Am J Pharm 2011; 30(10): 1934-1942.
Angel LB, Balza K, Perdomo LE, Dabian AS, Faría AR, Linero AR, Migliore B, Suárez H, Charris J, Israel A, Ramírez MM, Angel JE. Síntesis y evaluación farmacológica preliminar de nuevos compuestos quinolínicos con actividad anti Corea de Huntington. Rev Fac Farm 2015; 78(1-2):94-100.
Lucas G, De Deurwaerdère P, Caccia S, Spampinato U. The effect of serotonergic agents on haloperidol-induced striatal dopamine release in vivo: opposite role of Jeon BS, Jackson-Lewis SV, Burke RE. 6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration 1995; 4(2): 131-137. https://doi.org/10.1006/ neur.1995.0016
Ungerstedt U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 1968; 5(1): 107-110. https://doi.org/10.1016/0014-2999(68)90164-7
Meltzer HY. Serotonergic mechanisms as targets for existing and novel antipsychotics. Handb Exp Pharmacol 2012; 212: 87-124. https://doi.org/10.1007/978-3-642-25761-2_4
Ushijima I, Carino M, Horita A. Involvement of D1 and D2 dopamine systems in the behavioral effects of cocaine in rats. Pharmacol Biochem Behav 1995; 52(4):737-741. https://doi.org/10.1016/0091-3057(95)00167-U.5-HT and 5-HT
Simola N, Morelli M, Carta AR. The 6-hy- droxydopamine model of Parkinson’s disease. Neurotox Res 2007; 11(3-4): 151-167. https://doi.org/10.1007/BF03033565.
Thoenen H, Tranzer JP. Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-Hydroxydopamine. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 1968; 261(3): 271-288. https://doi.org/10.1007/BF00536990. Psychopharmacology 1984; 82(4): 409-410. https://doi.org/10.1007/BF00427697.
Nichols DE. The development of novel dopamine agonists. ACS Symp Ser Am Chem Soc 1983; 224(9): 201-221. https://doi. org/10.1021/bk-1983-0224.ch009.
Publicado
2023-03-01
Cómo citar
Velásquez, M. del V., Albarracín, A. E., Boscán, K., Ángel, L. B., Izquierdo, R. E., Ramírez, M. M., Migliore, B. del C., Charris, J. E., Garrido, M. del R., Israel, A., López, S. E., & Ángel, J. E. (2023). Efecto del compuesto N-2,6-dicloro-aralquil- 2-Aminoindano en la conducta estereotipada de ratas. Acción dopaminérgica selectiva central sobre los ganglios basales más que en las estructuras límbicas.: Effect of the compound N-2,6-dichloro-aralkyl-2-aminoindane on the stereotyped behavior of rats. Selective action on the central dopaminergic system in the basal ganglia over limbic structures. Investigación Clínica, 64(1), 15-27. https://doi.org/10.54817/IC.v64n1a02
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