Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores

European Journal of Medicinal Chemistry
B HoJ P Stables

Abstract

Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(alpha-methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the alpha-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50=5.8 mgkg(-1), TD50 =36.4 mgkg(-1), PI=6.3). Replacement of the piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with ...Continue Reading

References

Mar 1, 1976·Journal of Medicinal Chemistry·J M GrisarN L Wiech
Feb 7, 1992·Journal of Medicinal Chemistry·H W KleemannH Urbach
Aug 1, 1986·Journal of Medicinal Chemistry·C R ClarkR T Sansom
Sep 1, 1985·Journal of Medicinal Chemistry·C R ClarkG N Norris
Nov 1, 1982·Journal of Pharmaceutical Sciences·A M CriderC N Hinko
Mar 1, 1995·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·P Benetello
Feb 5, 1993·Journal of Medicinal Chemistry·R T ShumanP D Gesellchen
Jun 19, 2013·International Orthopaedics·Araceli Cuellar, A Hari Reddi

❮ Previous
Next ❯

Citations

Jun 24, 2005·Journal of Zhejiang University. Science. B·Navneet Aggarwal, Pradeep Mishra
Nov 18, 2015·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Goutam Brahmachari
Jul 10, 2008·Magnetic Resonance in Chemistry : MRC·Margit WinklerAlk Dransfeld
Apr 29, 2011·Organic & Biomolecular Chemistry·Muthupandi NagarajNattamai Bhuvanesh
May 2, 2013·Acta Crystallographica. Section E, Structure Reports Online·Sumati AnthalVivek K Gupta
Jun 3, 2015·Archiv der Pharmazie·Mohamed Nabil Aboul-EneinRasha Mohamed Hassan
Oct 31, 2012·Organic & Biomolecular Chemistry·Devdutt ChaturvediVirendra Mishra
Mar 2, 2021·Amino Acids·José Luis Viveros-CeballosMario Ordóñez
Jan 7, 2020·The Journal of Organic Chemistry·Derek A LeasJonathan L Vennerstrom

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.