Structure-activity studies on nifedipine in isolated cardiac muscle

Rodenkirchen, R; Bayer, R; Steiner, Rudolf; Bossert, F.; Meyer, H.; Möller, E

doi:10.1007/bf00499876

Cited by 75 publications

(24 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Changing the phenyl substituent is a potentially effective way of doing this. In conjunction with previous QSAR studies (20,(38)(39)(40), the unfavourable effect of substitution at the 4' position of the phenyl ring and of large substituents at the 3' position is underlined. The energy of the HOMO has been shown to be important.…”

Section: \ mentioning

confidence: 70%

“…The introduction of a substituent at the 4' position of the phenyl ring reduces the activity of the DHP. This appears in the model as the projected axial length of the 4' substituent and is expected from previous QSAR studies (20,(38)(39)(40). The length of the meta substituent and the energy of the HOMO are also included in the model.…”

Section: \ mentioning

confidence: 94%

“…The recent identification of the putative DHP binding site in a region of conserved sequence homology within the calcium channel protein suggests that the features of the DHP that interact with its receptor are similar in skeletal, cardiac, and neurologic calcium channels (37). Earlier structure-activity studies using empirical descriptors (20,(38)(39)(40) have attempted to define these features; typically these have used successively larger numbers of DHPs to improve the statistical treatment. The following attributes have been correlated to DHP bioactivity: (i) a hydrogen available for hydrogen bonding on the ring nitrogen (38); (ii) decreasing activity with increasing bulk (sterimol B 1) on para-substituted compounds and with increasing length (sterimol L) on meta-substituted compounds (20); (iii) lipophilicity effect of substituents on the phenyl ring (20,39,40); (iv) a related inductive effect of phenyl ring substituents (20); and (v) decreasing activity with increasing ester side-chain bulk (39).…”

Section: \ mentioning

confidence: 99%

See 2 more Smart Citations

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.

View full text Add to dashboard Cite

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]

show abstract

Section: \ mentioning

confidence: 70%

Section: \ mentioning

confidence: 94%

Section: \ mentioning

confidence: 99%

See 1 more Smart Citation

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.

View full text Add to dashboard Cite

show abstract

“…In a comparison of negative inotropic agents including both Ca2+ channel antagonists and unrelated compounds, a positive association for the latter compounds only was observed between activity and increasing hydrophobicity, suggestive of a membrane perturbant action . The most extensive structure-activity data are available for the 1,4-dihydropyridines and the data, derived from in vivo (Loev et al, 1974) and in vitro (Rodenkirchen et al, 1979;Bolger et al, 1983) pharma->,Na+…”

Section: Ca2+ Channel Antagonistsmentioning

confidence: 99%

Calcium channel antagonists: pharmacological considerations.

Rampe¹,

Su²,

Yousif³

et al. 1985

Brit J Clinical Pharma

View full text Add to dashboard Cite

“…When the action on the force ofcontraction is investigated in isolated heart preparations, no effects of nitrendipine can be detected in this concentration range. Nitrendipine starts to depress considerably the force of contraction only at a concentration of 10-M and displays an ED_0 of about 3 x 10-7 M (Rodenkirchen et al, 1979;McBride et al, 1984;Vaghy et al, 1984a,b). This discrepancy has been noticed earlier (e.g.…”

Section: Introductionmentioning

confidence: 98%

High and concentration‐proportional accumulation of [³H]‐nitrendipine by intact cardiac tissue

Lüllmann

Mohr

1987

British J Pharmacology

View full text Add to dashboard Cite

1 The binding of [3H]-nitrendipine to intact, electrically driven isolated left atria of guinea-pigs was investigated over the concentration range 10-10M to 3 x 10-lM. 2 A high affinity binding site saturable in the nM range as found in ventricular homogenates could not be detected. Instead the accumulation ofnitrendipine in intact atria was found to be proportional to the concentration from 10-"°M to 106m; beyond 10-6 M the binding started to become saturated.3 Nitrendipine was highly accumulated in atrial tissue. The cell:medium ratios amounted to about 120 in the range from 10-"M to 10-6M.4 The concentration-response curve for the negative inotropic action of nitrendipine yielded an ED_, of 3 x 10-M, thus lying within the range of concentration-proportional accumulation.5 The reduction of the contractile force proceeded faster (t,< Omin) than the uptake process (t -40 min) suggesting that it is the binding of nitrendipine into a superficial compartment, which interferes with the excitation-contraction coupling. 6 The results suggest that the high concentration of nitrendipine present in hydrophobic cellular compartments such as the plasmalemma might be involved in its pharmacological action.

show abstract

Structure-activity studies on nifedipine in isolated cardiac muscle

Cited by 75 publications

References 21 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

Calcium channel antagonists: pharmacological considerations.

High and concentration‐proportional accumulation of [³H]‐nitrendipine by intact cardiac tissue

Contact Info

Product

Resources

About

Structure-activity studies on nifedipine in isolated cardiac muscle

Cited by 75 publications

References 21 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

Calcium channel antagonists: pharmacological considerations.

High and concentration‐proportional accumulation of [3H]‐nitrendipine by intact cardiac tissue

Contact Info

Product

Resources

About

High and concentration‐proportional accumulation of [³H]‐nitrendipine by intact cardiac tissue