In vitro studies on L-771,688 (SNAP 6383), a new potent and selective α1A-adrenoceptor antagonist

被引:32
作者
Chang, RSL
Chen, TB
O'Malley, SS
Pettibone, DJ
DiSalvo, J
Francis, B
Bock, MG
Freidinger, R
Nagarathnam, D
Miao, SW
Shen, QR
Lagu, B
Dhar, TGM
Tyagarajan, S
Marzabadi, MR
Wong, WC
Gluchowski, C
Forray, C
机构
[1] Merck Res Labs, Dept Pharmacol, W Point, PA 19486 USA
[2] Synapt Pharmaceut Corp, Paramus, NJ USA
关键词
alpha(1A)-adrenoceptor; adrenoceptor; alpha(1A)-adrenoceptor antagonist; prostate; adrenoceptor subtype;
D O I
10.1016/S0014-2999(00)00854-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
L-771,688 (SNAP 6383, methyl(4S)-4-(3,4-difluorophenyl)-6-[(methyloxy)methyl]-2-oxo-3-[({3-[4-(2-pyridinyl)-1- piperidinyl]propyl)amino)carbonyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate) had high affinity(K-i less than or equal to 1 nM) for [H-3]prazosin binding to cloned human, rat and dog alpha (1A)-adrenoceptors and high selectivity (> 500-fold) over alpha (1B) and alpha (1D)-adrenoceptors. [H-3]Prazosin/(+/-)-beta[I-125]-4-hydroxy-phenyl)-ethyl-aminomethyl-teralone([I-125]HEAT) binding studies in human and animal tissues known to contain alpha (1A) and non-alpha (1A)-adrenoceptors further demonstrated the potency and alpha (1A)-subtype selectivity of L-771,688. [H-3]L-771,688 binding studies at the cloned human alpha (1A)-adrenoceptors and in rat tissues indicated that specific [H-3]L-771,688 binding was saturable and of high affinity(K-d = 43-90 pM) and represented binding to the pharmacologically relevant alpha (1A)-adrenoceptors. L-771,688 antagonized norepinephrine-induced inositol-phosphate responses in cloned human alpha (1A)-adrenoceptors, as well as phenylephrine or A-61603 (N-[5-4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-terahydro-naphthlen-1-yl] methanesulfonamide hydrobromide) induced contraction in isolated rat, dog and human prostate, human and monkey bladder neck and rat caudal artery with apparent K-b values of 0.02-0.28 nM. In contrast, the contraction of rat aorta induced by norepinephrine was resistant to L-771,688. These data indicate that L-771,688 is a highly selective alpha (1A)-adrenoceptor antagonist. (C) 2000 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:301 / 312
页数:12
相关论文
共 35 条
[1]  
Adkison K K, 1998, Pharm Biotechnol, V11, P423
[2]  
Akiyama K, 1999, J PHARMACOL EXP THER, V291, P81
[3]   FUNCTIONAL EVIDENCE EQUATING THE PHARMACOLOGICALLY-DEFINED ALPHA(1A)-ADRENOCEPTOR AND CLONED ALPHA(1C)-ADRENOCEPTOR - STUDIES IN THE ISOLATED-PERFUSED KIDNEY OF RAT [J].
BLUE, DR ;
BONHAUS, DW ;
FORD, APDW ;
PFISTER, JR ;
SHARIF, NA ;
SHIEH, IA ;
VIMONT, RL ;
WILLIAMS, TJ ;
CLARKE, DE .
BRITISH JOURNAL OF PHARMACOLOGY, 1995, 115 (02) :283-294
[4]  
Broten T, 1999, FASEB J, V13, pA142
[5]  
Bylund D.B., 1998, ADRENOCEPTORS IUPHAR, P58
[6]  
Chang R. S. L., 1996, FASEB Journal, V10, pA424
[7]  
Chang RSL, 1998, N-S ARCH PHARMACOL, V358, pR593
[8]   IN-VITRO PHARMACOLOGY OF MK-996, A NEW POTENT AND SELECTIVE ANGIOTENSIN-II (AT(1)) RECEPTOR ANTAGONIST [J].
CHANG, RSL ;
BENDESKY, RJ ;
CHEN, TB ;
FAUST, KA ;
KLING, PJ ;
OMALLEY, SA ;
NAYLOR, EM ;
CHAKRAVARTY, PK ;
PATCHETT, AA ;
GREENLEE, WJ ;
CLINESCHMIDT, BV ;
LOTTI, VJ .
DRUG DEVELOPMENT RESEARCH, 1994, 32 (03) :161-171
[9]  
CHAPPLE CR, 1995, BRIT J UROL, V76, P47
[10]   Design and synthesis of novel α1a adrenoceptor-selective antagonists.: 2.: Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety [J].
Dhar, TGM ;
Nagarathnam, D ;
Marzabadi, MR ;
Lagu, B ;
Wong, WC ;
Chiu, G ;
Tyagarajan, S ;
Miao, SW ;
Zhang, FQ ;
Sun, WY ;
Tian, D ;
Shen, QR ;
Zhang, J ;
Wetzel, JM ;
Forray, C ;
Chang, RSL ;
Broten, TP ;
Schorn, TW ;
Chen, TB ;
O'Malley, S ;
Ransom, R ;
Schneck, K ;
Bendesky, R ;
Harrell, CM ;
Vyas, KP ;
Zhang, KY ;
Gilbert, J ;
Pettibone, DJ ;
Patane, MA ;
Bock, MG ;
Freidinger, RM ;
Gluchowski, C .
JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (23) :4778-4793