Raimund Mannhold

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A pattern analysis of inotropic actions was carried out on isotonically shortening cat papillary muscles exposed to (±)-verapamil and (±)-D 600 and compared to other Ca-antagonistic interventions. 1. (±)-Verapamil (1–5 μg/ml) leaves contraction amplitudes nearly unchanged at 6/min, whereas at 60/min more than 90% depression (5 μ/ml) occurs. (±)-D 600 is(More)
ATP-sensitive potassium channels (K(ATP) channels) are heteromeric complexes of pore-forming inwardly rectifying potassium channel subunits and regulatory sulfonylurea receptor subunits. K(ATP) channels were identified in a variety of tissues including muscle cells, pancreatic beta-cells, and various neurons. They are regulated by the intracellular ATP/ADP(More)
We first review the state-of-the-art in development of log P prediction approaches falling in two major categories: substructure-based and property-based methods. Then, we compare the predictive power of representative methods for one public (N = 266) and two in house datasets from Nycomed (N = 882) and Pfizer (N = 95809). A total of 30 and 18 methods were(More)
Fendiline is an anti-anginal agent for the treatment of coronary heart disease. Together with other diphenylalkylamines it is sub-classified in the group of lipophilic calcium antagonists. It binds to the calcium channel and to calmodulin with rather similar affinities. Pharmaco-dynamically, it exerts the typical calcium as well as calmodulin antagonistic(More)
The key importance of lipophilicity in bio-studies is discussed for beta-blockers. Examples of their lipophilicity-dependent pharmacological properties including pharmacokinetic, pharmacodynamic and clinical aspects are reviewed. Comprehensive lipophilicity compilations of beta-blockers are lacking so far. LogP calculations with 10 programs for 30(More)
A large variety of log P calculation methods failed to produce sufficient accuracy in log P prediction for two in-house datasets of more than 96000 compounds contrary to their significantly better performances on public datasets. The minimum Root Mean Squared Error (RMSE) of 1.02 and 0.65 were calculated for the Pfizer and Nycomed datasets, respectively, in(More)
An investigation was carried out towards a qualitative and quantitative structure-activity relationship of verapamil based on an analysis of the frequency-dependent negative inotropic action exerted in cat papillary muscles by various groups of verapamil derivatives. (1) Substituents of the benzene ring near the asymmetric carbon atom and the isopropyl(More)
Two experimental (log P, R(Mw)) and 17 calculation descriptors for molecular lipophilicity (fragmental, atom-based or based on molecular properties) were investigated by multvariate analysis for a database of 159 compounds including both simple structures as well as more complex drug molecules. Principal component analysis (PCA) of the entire database(More)
About 20 non-peptide angiotensin II receptor antagonists are in various stages of clinical development. Different modeling approaches were used to predict the pharmacophoric requirements for AT(1) (angiotensin II receptor subtype 1) affinity. However, to our knowledge, none was used to predict both the selectivity toward AT(1) and AT(2) (angiotensin II(More)
Ligand-based virtual screening approaches were applied to search for new chemotype KCOs activating Kir6.2/SUR1 KATP channels. A total of 65 208 commercially available compounds, extracted from the ZINC archive, served as database for screening. In a first step, pharmacokinetic filtering via VolSurf reduced the initial database to 1913 compounds. Afterward,(More)