1,4-Dihydropyridine antagonist activities at the calcium channel: a quantitative structure-activity relationship approach

Coburn, Robert A.; Wierzba, Mark; Suto, Mark J.; Solo, A. J.; Triggle, A.M.; Triggle, David J.

doi:10.1021/jm00119a009

Cited by 121 publications

(91 citation statements)

References 2 publications

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“…In such a case, a priori preference for sp/sp ester orientation may predispose the DHPs to bind at their receptor. Notably, the 2'-amino and 3'-acetyl substituted DHPs had sp/ap ester orientation in their energetically favoured conformzition; they are both weakly active DHPs (20).…”

Section: Energies Of Conformersmentioning

confidence: 99%

“…(20). These data were acquired using a standard protocol that measured the inhibition of smooth muscle contraction by calcium channel blockade.…”

Section: Statistical Stt-~tcture-activity Relationship Calculationsmentioning

confidence: 99%

“…These descriptors were then fit to pharmacologic activity (obtained from ref. 20 as -log EC,,) using linear regression. This procedure was applied to subgroups of compounds substituted at the 2', the 3', and the 4' positions of the phenyl ring, to those substituted at either the 2' or 3' positions on the phenyl ring, and to the entire data set of 34 compounds.…”

Section: Statistical Stt-~tcture-activity Relationship Calculationsmentioning

confidence: 99%

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Theoretical studies applicable to the design of novel anticonvulsants: an AM1 molecular orbital structure–activity study of dihydropyridine calcium channel antagonists

Bikker¹,

Weaver²

1992

Can. J. Chem.

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Can. J. Chem. 70, 2449 (1992. The development and synthesis of anticonvulsant new chemical entities that are distinct from the cyclic ureides in current clinical use is a continuing neuropharmacologic priority. The design of neuronal specific dihydropyridines active at the L-type calcium channel protein represents a rational approach to this design problem. To provide the structural data required for the design of anticonvulsant dihydropyridines, an AM1 semi-empirical molecular orbital study has been undertaken. Forty-six dihydropyridine calcium channel antagonists have been fully optimized at the AM1 level. Each of the 46 analogues was considered in six conformations to provide a systematic evaluation of changes in ester and phenyl ring orientation. The calculational validity of the AM1 Hamiltonian when applied to dihydropyridines was demonstrated by comparing AM l-optimized structures to experimental (X-ray crystallographic) and nb initio molecular orbital (ST0 3G basis set) geometries. For each dihydropyridine, 79 AM1-derived geometric and electronic descriptors were obtained. The resulting descriptor matrix comparing structural descriptors with biological activity was statistically reduced to provide regression and discriminant structure-activity models for dihydropyridine calcium channel antagonism.JACK ANDREW BIKKER et DONALD FREDRIC WEAVER. Can. J. Chem. 70, 2449 (1992). Le developpement et la synthkse de nouvelles entitCs chimiques anticonvulsives distinctes des urCides cycliques actuellement en usage clinique sont des priorites neuropharmacologiques permanentes. La conception de dihydropyridines de specificit6 neuronale, actives au niveau de la protkine de type L du canal du calcium, reprCsente une approche rationnelle a ce problkme. Afin d'obtenir les donnCes structurales necessaires pour la conception de dihydropyridines anticonvulsives, on a entrepris une etude d'orbitales molCculaires semi-empiriques AMI. OpCrant au niveau AMI, on a optimisC 46 dihydropyridines antagonistes du canal du calcium. Afin d'obtenir une &valuation systkmatique des changements dans I'orientation de I'ester et du noyau phCnyle, on a considCrC chacun de ces 46 analogues dans six conformations. On a dCmontrC que I'hamiltonien AM1 applique aux dihydropyridines est valide pour les calculs en procCdant a une comparaison des structures optimisees par AM1 avec celles obtenues expCrimentalement (diffraction des rayons X) et avec les gComCtries obtenues par des calculs d'orbitales niolCculaires ah irzitio (base S T 0 3G). Pour chaque dihydropyridine, on a obtenu 79 descripteurs gComCtriques et Clectroniques derivCs du AMI. On a reduit statistiquement la matrice resultante de descripteurs comparant les descripteurs structuraux avec I'activite biologique afin d'obtenir des modkles de regression et d'activitC-structure discriminatoires pour la dihydropyridine antagoniste du canal du calcium.[Traduit par la redaction]

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Section: Energies Of Conformersmentioning

confidence: 99%

“…(20). These data were acquired using a standard protocol that measured the inhibition of smooth muscle contraction by calcium channel blockade.…”

Section: Statistical Stt-~tcture-activity Relationship Calculationsmentioning

confidence: 99%

Section: Statistical Stt-~tcture-activity Relationship Calculationsmentioning

confidence: 99%

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Theoretical studies applicable to the design of novel anticonvulsants: an AM1 molecular orbital structure–activity study of dihydropyridine calcium channel antagonists

Bikker¹,

Weaver²

1992

Can. J. Chem.

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“…[5][6][7][8] Also, a number of DHP derivatives are employed as potential drug candidates for the treatment of congestive heart failure. 9 1,8-Dioxodecahydroacridines and their derivatives are polyfunctionalized 1,4-dihydropyridine derivatives which have received less attention than other 1,4-dihydropyridine derivatives.…”

Section: Introductionmentioning

confidence: 99%

Carbon-Based Solid Acid as an Efficient and Reusable Catalyst for the Synthesis of 1,8-Dioxodecahydroacridines Under Solvent-Free Conditions

Davoodnia¹,

Khojastehnezhad²,

Tavakoli‐Hoseini³

2011

Bulletin of the Korean Chemical Society

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Carbon-based solid acid catalyst was found to be highly efficient, eco-friendly and recyclable heterogeneous catalyst for the multicomponent reaction of dimedone, aromatic aldehydes, and a nitrogen source (ammonium acetate or aromatic amines) under solvent-free conditions, giving rise to 1,8-dioxodecahydroacridines in high yields. The present methodology offers several advantages, such as a simple procedure with an easy work-up, short reaction times, high yields, and the absence of any volatile and hazardous organic solvents.

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“…The presence of one or more electron-att racting substituents at the ortho-or meta-position of the phenyl ring increases the activity (8). Ester groups at C-3 and C-5 are in turn very important for modulating activity and tissue selectivity.…”

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confidence: 99%

Synthesis and photodegradation studies of analogues of muscle relaxant 1,4-dihydropyridine compounds

et al. 2017

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This paper describes the synthesis of 1,4-dihydropyridine compounds (DHPs) endowed with good muscle relaxant activity and stability to light. Six new condensed DHPs were synthesized by the microwave irradiation method. A long-chain ester moiety [2-(methacryloyloxy)ethyl] and various substituents on the phenyl ring were demonstrated to aff ect the muscle relaxant activity occurring in isolated rabbit gastric fundus smooth muscle strips. Forced photodegradation conditions were applied to the molecules according to the ICH rules. The degradation profi le of the drugs was monitored by spectrophotometry coupled with the multivariate curve resolution technique. Formation of the oxidized pyridine derivative was observed for all the studied DHPs, except for one compound, which showed very fast degradation and formation of a second photoproduct. Pharmacological tests on the molecules showed a good muscle relaxing eff ect, with a mechanism similar to that of nifedipine, however, proving to be more stable to light.

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1,4-Dihydropyridine antagonist activities at the calcium channel: a quantitative structure-activity relationship approach

Cited by 121 publications

References 2 publications

Theoretical studies applicable to the design of novel anticonvulsants: an AM1 molecular orbital structure–activity study of dihydropyridine calcium channel antagonists

Theoretical studies applicable to the design of novel anticonvulsants: an AM1 molecular orbital structure–activity study of dihydropyridine calcium channel antagonists

Carbon-Based Solid Acid as an Efficient and Reusable Catalyst for the Synthesis of 1,8-Dioxodecahydroacridines Under Solvent-Free Conditions

Synthesis and photodegradation studies of analogues of muscle relaxant 1,4-dihydropyridine compounds

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