Pharmaceutical evaluation of naftopidil enantiomers: Rat functional assays in vitro and estrogen/androgen induced rat benign prostatic hyperplasia model in vivo.
Naftopidil (NAF) is a α1D/1Aadrenoceptor selective drug used for the treatment of both benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS). However, NAF is used as a racemate in clinic. To compare the differences and similarities among two enantiomers and racemate, pharmacological activities were evaluated through rat functional assays in vitro and estrogen/androgen (E/T) induced rat BPH model in vivo. NAF and the two enantiomers showed similar blocking activity on α1receptor. S-NAF exhibited more α1D/1Aadrenoceptor subtype selectivity than R-NAF and the racemate. The selectivity ratios pA2(α1D)/pA2(α1B) and pA2(α1A)/pA2(α1B) were 40.7- and 16.2-fold, respectively. NAF and its enantiomers effectively prevented the development of rat prostatic hyperplasia via suppressing the increase of the prostatic wet weight, visually. The quantitative analysis of the relative acinus volume, relative stroma volume, relative epithelial volume, epithelial height and expression of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) were carried out. S-NAF showed an advantage on the effect of inhibiting prostate wet weight and stroma volume over R-NAF and racemate NAF (P<0.05). Nevertheless, no other significant difference was observed between these two enantiomers. In conclusion, both R-NAF and S-NAF not only relax prostate muscle but also inhibit the prostate growth, thus relieve BPH.
Center of Pharmaceutical Research and Development, School of Pharmacy, Guangzhou Medical University, Guangzhou 511400, PR China. Electronic address: huangjunjun1985@sina.com.
Jun-Jun
JJ
Huang
Center of Pharmaceutical Research and Development, School of Pharmacy, Guangzhou Medical University, Guangzhou 511400, PR China.
Yi
Y
Cai
Guangdong PeiZheng College, Guangzhou 510830, PR China.
Yan-Zhen
YZ
Yi
The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, PR China.
Min-Yi
MY
Huang
Center of Pharmaceutical Research and Development, School of Pharmacy, Guangzhou Medical University, Guangzhou 511400, PR China.
Liu
L
Zhu
Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Department of Plant Pathology, South China Agricultural University, Guangzhou 510642, PR China.
Fei
F
He
Center of Pharmaceutical Research and Development, School of Pharmacy, Guangzhou Medical University, Guangzhou 511400, PR China.
Xia-Wen
XW
Liu
Center of Pharmaceutical Research and Development, School of Pharmacy, Guangzhou Medical University, Guangzhou 511400, PR China.
Bi-Yun
BY
Huang
Center of Pharmaceutical Research and Development, School of Pharmacy, Guangzhou Medical University, Guangzhou 511400, PR China. Electronic address: mryuanmu838@sina.com.
Mu
M
Yuan
D000199:Actins / Q000378:metabolism; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004967:Estrogens / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D009929:Organ Size / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000199:Actins; D058668:Adrenergic alpha-1 Receptor Antagonists; D000728:Androgens; D004967:Estrogens; D009281:Naphthalenes; D010879:Piperazines; D018809:Proliferating Cell Nuclear Antigen; C064357:naftopidil
Benign prostatic hyperplasia; Estrogen/androgen; Naftopidil enantiomers; α(1) adrenoceptor blocker