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

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.