Pharmacological analysis of the novel, selective α1‐adrenoceptor antagonist, KMD‐3213, and its suitability as a tritiated radioligand

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Abstract
Pharmacological profiles of tritiated KMD-3213, a new antagonist of alpha1-adrenoceptor (AR), were examined in recombinant and native alpha1-AR, and compared with those of prazosin (PZ) and tamsulosin (YM-617). In saturation experiments, [3H]-KMD (10-2000 pM) showed high affinity for alpha1a-AR (pK(D) = 10.5). However, no significant binding to alpha1b-AR and insufficient/unsaturated binding to alpha1d-AR were observed at concentrations up to 2000 pM. In contrast, [3H]-PZ and [3H]-YM bound to all subtypes with high affinity (pK(D)>9). In competition experiments, KMD-3213 also had higher affinity for alpha1a-AR than for other two subtypes; pKi = 10.4, 8.1 and 8.6 for alpha1a-, alpha1b- and alpha1d-AR, respectively. [3H]-KMD also bound to the native alpha1A-AR (rat submaxillary gland) with high affinity, but not to alpha1B-AR (rat liver). In rat kidney which expresses alpha1A- and alpha1B-AR, [3H]-KMD and [3H]-PZ bound to a single high-affinity site (pK(D) = 10.8 and 10.1, respectively) with distinct amount of binding sites (Bmax = 159 and 267 fmol mg(-1) protein, respectively). [3H]-PZ binding sites consisted of low- and high-affinity sites for KMD-3213 (pKi = 7.6 and 10.7, respectively), for WB4101 (pK = 8.1 and 10.0) and for YM-617 (pKi = 8.7 and 10.8). The proportion of the high affinity site was approximately 60% in these drugs which was compatible to the ratio between Bmax of [3H]-KMD and [3H]-PZ. [3H]-KMD binding sites consisted of a single site for these drugs with affinities which were similar to those of the high affinity sites in [3H]-PZ binding. In functional experiments, KMD-3213 antagonized the contractile responses to NS-49 or noradrenaline (NA) with higher affinity in functional alpha1A- (rat caudal artery, pA2= 10.0 against NS-49) and alpha1L-AR (dog mesenteric artery, pA2 = 9.9 against NA) than in alpha1B- (dog carotid artery, pA2 = 7.7 against NA) and alpha1D-AR (rat thoracic aorta, pA2 = 8.3 against NA). These results confirm the alpha1A-AR selectivity and high affinity of KMD-3213, and indicate that [3H]-KMD can label selectively alpha1A-AR.

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