Design, synthesis, and pharmacological evaluation of conformationally constrained analogues of N,N'-diaryl- and N-aryl-N-aralkylguanidines as potent inhibitors of neuronal Na+ channels
Details
Serval ID
serval:BIB_1E7D291E0C19
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Design, synthesis, and pharmacological evaluation of conformationally constrained analogues of N,N'-diaryl- and N-aryl-N-aralkylguanidines as potent inhibitors of neuronal Na+ channels
Journal
Journal of Medicinal Chemistry
ISSN
0022-2623 (Print)
Publication state
Published
Issued date
07/1998
Volume
41
Number
16
Pages
3048-61
Notes
Journal Article --- Old month value: Jul 30
Abstract
In the present investigation, the rationale for the design, synthesis, and biological evaluation of potent inhibitors of neuronal Na+ channels is described. N,N'-diaryl- and N-aryl-N-aralkylguanidine templates were locked in conformations mimicking the permissible conformations of the flexible diarylguanidinium ion (AS+, AA+, SS+). The resulting set of constrained guanidines termed "lockamers" (cyclophane, quinazoline, aminopyrimidazolines, aminoimidazolines, azocino- and tetrahydroquinolinocarboximidamides) was examined for neuronal Na+ channel blockade properties. Inhibition of [14C]guanidinium ion influx in CHO cells expressing type IIA Na+ channels showed that the aminopyrimidazoline 9b and aminoimidazoline 9d, compounds proposed to lock the N,N'-diarylguanidinium in an SS+ conformation, were the most potent Na+ channel blockers with IC50's of 0.06 microM, a value 17 times lower than that of the parent flexible compound 18d. The rest of the restricted analogues with 4-p-alkyl substituents retained potency with IC50 values ranging between 0.46 and 2.9 microM. Evaluation in a synaptosomal 45Ca2+ influx assay showed that 9b did not exhibit high selectivity for neuronal Na+ vs Ca2+ channels. The retention of significant neuronal Na+ blockade in all types of semirigid conformers gives evidence for a multiple mode of binding in this class of compounds and can possibly be attributed to a poor structural specificity of the site(s) of action. Compound 9b was also found to be the most active compound in vivo based on the high level of inhibition of seizures exhibited in the DBA/2 mouse model. The pKa value of 9b indicates that 9b binds to the channel in its protonated form, and log D vs pH measurements suggest that ion-pair partitioning contributes to membrane transport. This compound stands out as an interesting lead for further development of neurotherapeutic agents.
Keywords
Animals
Anticonvulsants/chemical synthesis/chemistry/metabolism/pharmacology
Biological Transport
Brain/drug effects/metabolism/ultrastructure
CHO Cells
Calcium/metabolism
Calcium Channel Blockers/chemical
synthesis/chemistry/metabolism/pharmacology
Calcium Channels/drug effects
Cricetinae
*Drug Design
Female
Guanidine/metabolism
*Imidazoles/chemical synthesis/chemistry/metabolism/pharmacology
Male
Mice
Mice, Inbred DBA
Molecular Conformation
Neurons/*drug effects/metabolism
*Pyrimidines/chemical synthesis/chemistry/metabolism/pharmacology
Rats
Receptors, N-Methyl-D-Aspartate/metabolism
Seizures/prevention & control
*Sodium Channel Blockers
Sodium Channels/biosynthesis
Structure-Activity Relationship
Synaptosomes/drug effects/metabolism
Pubmed
Web of science
Create date
25/01/2008 13:59
Last modification date
20/08/2019 13:54