Binding studies and GRIND/ALMOND-based 3D QSAR analysis of benzothiazine type K(ATP)-channel openers.
For seventeen 1,4-benzothiazine potassium channel openers, we performed binding studies in rat aortic smooth muscle cells and cardiomyocytes, compared their binding affinities with published relaxation data, and derived 3D-QSAR models using GRIND/ALMOND descriptors. Binding affinities in smooth muscle cells range from a pK(D) of 4.76 for compound 3e to 9.10 for compound 4c. Comparison of data for smooth muscle relaxation and binding shows preferentially higher pEC(50)s for the former. In cardiomyocytes, pK(D) values range from 4.21 for 3e to 8.16 for 4c. 3D-QSAR analysis resulted in PLS models of two latent variables for all three activities with determination coefficients of 0.97 (smooth muscle relaxation) and 0.94 (smooth muscle cells- and cardiomyocytes-binding). Internal validation yielded q(2) values of 0.69, 0.66, and 0.64. The carbonyl on the N-4 substituent, the hydrogen bond acceptor at C-6, the five-membered ring at N-4, and the gem-dimethyls mainly guide strong binding and strong smooth muscle relaxation.
Laboratorio di Chemiometria e Chemioinformatica, Dipartimento di Chimica, Università di Perugia, Via Elce di Sotto 10, I-06123 Perugia, Italy.
Emanuele
E
Carosati
Horst
H
Lemoine
Roberto
R
Spogli
Dagmar
D
Grittner
Raimund
R
Mannhold
Oriana
O
Tabarrini
Stefano
S
Sabatini
Violetta
V
Cecchetti
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects* / Q000502:physiology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
C446962:1,4-benzothiazine; D015221:Potassium Channels; D013843:Thiazines; D000255:Adenosine Triphosphate