title: Structure-activity relationships of receptor binding of 1,4-dihydropyridine derivatives.
abstract: The present study was undertaken to investigate binding activity of synthesized 1,4-dihydropyridine (1,4-DHP) derivatives (Compounds 1--124) to 1,4-DHP calcium channel antagonist receptors in rat brain. Sixteen 1,4-DHP derivatives inhibited specific (+)-[3H]PN 200-110 binding in rat brain in a concentration-dependent manner with IC50 value of 0.43 to 3.49 microM. Scatchard analysis revealed that compounds 54, 69, 85, like nifedipine, caused a significant increase in apparent dissociation constant (Kd) for (+)-[3H]PN 200-110, while compounds 68, 69 and 80 caused a significant decrease in maximal number of bindings sites (Bmax). These data suggest that compounds 68, 69 and 80 exert longer-acting antagonistic effects of 1,4-DHP receptors than compounds 54, 69 and 85. The structure-activity relationship study has revealed that 1) ester groups in 3- and 5-positions are the most effective, 2) the aryl group in the 4-position of 1,4-DHP ring is the basic requirement for optimal activity, 3) position and type of electron-withdrawing groups on phenyl group at position 4 would affect the receptor-binding activity. Furthermore, compound 58 exerted alpha1 receptor binding activity, being 1.6 times greater than 1,4-DHP receptors. Compounds 81, 84, 91, 94, 106, 108 and 109 showed significant binding of ATP-sensitive potassium (K ATP) channel, and the binding activities of compounds 81, 84, 108 and 109 were 1.6--3.8 times greater than the binding activity for 1,4-DHP receptors. Compounds 91 and 106 had similar binding activity for K ATP channel and 1,4-DHP receptors. In conclusion, the present study has shown that novel 1,4-DHP derivatives exert relatively high binding affinity to 1,4-DHP receptors and has revealed new aspect of structure-activity relationships of 1,4-DHP derivatives, especially hexahydroquinoline derivatives.
authors.forename: Daiki
authors.initials: D
authors.lastname: Takahashi
authors.forename: Luvsandorj
authors.initials: L
authors.lastname: Oyunzul
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Shinya
authors.initials: S
authors.lastname: Uchida
authors.forename: Rahime
authors.initials: R
authors.lastname: Simsek
authors.forename: Miyase Gozde
authors.initials: MG
authors.lastname: Gunduz
authors.forename: Chiat
authors.initials: C
authors.lastname: Safak
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D054086:KATP Channels / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D011983:Receptors, Purinergic / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D054086:KATP Channels; D011941:Receptors, Adrenergic; D011978:Receptors, Nicotinic; D011983:Receptors, Purinergic; C038806:1,4-dihydropyridine