Structure-Activity Relationships of Polycyclic Aromatic Amines with Calcium Channel Blocking Activity

Malan, Sarel F.; Walt, J. J. Van der; Schyf, Cornelius J. Van der

doi:10.1002/(sici)1521-4184(200001)333:1<10::aid-ardp10>3.0.co;2-5

Cited by 28 publications

(27 citation statements)

References 23 publications

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“…More recently, several other pentacyclics (Malan et al, 1996;Malan et al, 2000;Malan et al, 2003) have been synthesized and evaluated for various biological activities. Foremost amongst these was the evaluation of the N-substituted 8,11-oxapentacylco undecanes 14 for ion channel activity where potential-dependent blocking of L-type Ca 2+ channels was observed (Malan et al, 1996;Malan et al, 2000).…”

Section: Diverse Activities For Related Pentacyclic Compoundsmentioning

confidence: 99%

“…Foremost amongst these was the evaluation of the N-substituted 8,11-oxapentacylco undecanes 14 for ion channel activity where potential-dependent blocking of L-type Ca 2+ channels was observed (Malan et al, 1996;Malan et al, 2000). The pentacycloundecane derivatives of 14 have also been shown to effectively cross the blood-brain barrier (Zah et al, 2003) and show potential as carriers for the delivery of drugs with low blood-brain barrier permeability.…”

Section: Diverse Activities For Related Pentacyclic Compoundsmentioning

confidence: 99%

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Medicinal chemistry of polycyclic cage compounds in drug discovery research

Oliver

Malan

2007

Med Chem Res

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Section: Diverse Activities For Related Pentacyclic Compoundsmentioning

confidence: 99%

Section: Diverse Activities For Related Pentacyclic Compoundsmentioning

confidence: 99%

Medicinal chemistry of polycyclic cage compounds in drug discovery research

Oliver

Malan

2007

Med Chem Res

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“…The NGP1-01 related polycyclic cage compound 6-benzylamino-3-hydroxyhexacyclo [6.5.0.0 3,7 .0 4,12 .0 5,10 .0 9,13 ] tridecane (1, Table 3) shows interaction at multiple receptors [66,67]. Electrophysiological evaluation of 1 for calcium, potassium and sodium channel block in guinea pig cardiac papillary muscle indicated that this compound, at test concentrations of 10-50 μM, inhibited the ion currents for Ltype calcium channels, sodium channels, and the fast component of the delayed rectifier potassium channel.…”

Section: Fig (2) Calcium Overload As a Results Of Excitotoxicity Leamentioning

confidence: 99%

Novel Multifunctional Anti-Alzheimer Drugs with Various CNS Neurotransmitter Targets and Neuroprotective Moieties

Schyf¹,

Mandel²,

Geldenhuys³

et al. 2007

CAR

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Traditionally, drug design programs are focused on optimizing the specificity of lead compounds against a carefully selected drug target. Disappointingly, this approach to discover a "magic bullet" drug has not met with the expected success for CNS disorders. Transcriptomics and proteomic profiling of neurodegenerative diseases have indicated that they are poly-etiological in origin and that the processes leading to neuronal death are multifactorial. An emerging concept is the design of drug ligands that modulate multiple drug targets identified for a particular disease. In this review we explore some examples of multifunctional drugs which may be useful in the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.

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“…Similar to other L-type calcium channel antagonists, steric considerations in NMDA receptor antagonism again appeared to be more important than electronic effects. 41 An increase in the polycyclic cage size from a pentacycloundecane structure to a tridecane structure 3 was accompanied by a 10-fold decrease in potency (2.98 M for 2 vs 36.22 M for 3) (FIG. 5).…”

Section: Figmentioning

confidence: 99%

“…41 Whole-cell voltage clamp experiments on guinea pig ventricular myocytes were again used to examine the calcium-channel blocking effects for this set of compounds. Structure-activity relationships (SAR) found in the series appeared to be dominated by geometric or steric constraints rather than by electronic considerations.…”

Section: Pentacycloundecane Aminesmentioning

confidence: 99%

Polycyclic Compounds: Ideal Drug Scaffolds for the Design of Multiple Mechanism Drugs?

Schyf

Geldenhuys

2009

Neurotherapeutics

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Summary:Recently there has been a resurging interest in developing multi-functional drugs to treat diseases with complex pathological mechanisms. Such drug molecules simultaneously target multiple etiologies that have been found to be important modulators in specific diseases. This approach has significant promise and may be more effective than using one compound specific for one drug target or, by a polypharmaceutical approach, using a cocktail of two or more drugs. Polycyclic ring structures are useful as starting scaffolds in medicinal chemistry programs to develop multi-functional drugs, and may also be useful moieties added to existing structures to improve the pharmacokinetic properties of drugs currently used in the clinic or under development. This review attempts to provide a synopsis of current published research to exemplify the use of polycyclic compounds as starting molecules to develop multi-functional drugs.

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Structure-Activity Relationships of Polycyclic Aromatic Amines with Calcium Channel Blocking Activity

Cited by 28 publications

References 23 publications

Medicinal chemistry of polycyclic cage compounds in drug discovery research

Medicinal chemistry of polycyclic cage compounds in drug discovery research

Novel Multifunctional Anti-Alzheimer Drugs with Various CNS Neurotransmitter Targets and Neuroprotective Moieties

Polycyclic Compounds: Ideal Drug Scaffolds for the Design of Multiple Mechanism Drugs?

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