Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.
A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.
Wong
W C
WC
Department of Urology, New York University Medical Center, New York, New York 10021, USA.
Chiu
G
G
Wetzel
J M
JM
Marzabadi
M R
MR
Nagarathnam
D
D
Wang
D
D
Fang
J
J
Miao
S W
SW
Hong
X
X
Forray
C
C
Vaysse
P J
PJ
Branchek
T A
TA
Gluchowski
C
C
Tang
R
R
Lepor
H
H
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects* / Q000503:physiopathology; D011470:Prostatic Hyperplasia / Q000503:physiopathology; D011725:Pyridines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*
C113173:5-(aminocarbonyl)-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)-(3-(4,4-diphenylpiperidin-1-yl)propyl); C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D015220:Calcium Channels; D010880:Piperidines; D011725:Pyridines; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine