Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist.
The in vitro and in vivo pharmacological profile of SB 223412 [(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carbo xamide], a novel human NK-3 (hNK-3) receptor antagonist, is described. SB 223412 demonstrated enantioselective affinity for inhibition of [125I][MePhe7]neurokinin B (NKB) binding to membranes of CHO cells expressing the hNK-3 receptor (CHO hNK-3). SB 223412, the (S)-isomer, (Ki = 1.0 nM), has similar affinity as the natural ligand, NKB (Ki = 0.8 nM) and another nonpeptide NK-3 receptor antagonist, SR 142801 (Ki = 1.2 nM). SB 223412 was selective for hNK-3 receptors compared with hNK-1 (>10,000-fold selective) and hNK-2 receptors (>140-fold selective), and selectivity was further demonstrated by its lack of effect, in concentrations up to 1 or 10 microM, in >60 receptor, enzyme and ion channel assays. SB 223412 enantioselectively inhibited the NKB-induced Ca++ mobilization in HEK 293 cells stably expressing the hNK-3 receptor. SB 223412 (10-1,000 nM) produced concentration-dependent rightward shifts in NKB-induced Ca++ mobilization concentration-response curves with a Kb value of 3 nM. In addition, SB 223412 antagonized senktide-induced contraction in the isolated rabbit iris sphincter muscle (Kb = 1.6 nM). In mice, oral administration of SB 223412 produced dose-dependent inhibition of behavioral responses induced by the NK-3 receptor-selective agonist, senktide (ED50 = 12.2 mg/kg). Pharmacokinetic evaluation of SB 223412 in rat and dog indicated low plasma clearance, oral bioavailability and high and sustained plasma concentrations after 4 to 8 mg/kg oral dosages. The preclinical profile of SB 223412 (high affinity, selectivity, reversibility and oral activity) suggests that it will be a useful tool compound to define the physiological and pathophysiological roles of NK-3 receptors.
Sarau
H M
HM
Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Skip_Sarau-1@sbphrd.com
Griswold
D E
DE
Potts
W
W
Foley
J J
JJ
Schmidt
D B
DB
Webb
E F
EF
Martin
L D
LD
Brawner
M E
ME
Elshourbagy
N A
NA
Medhurst
A D
AD
Giardina
G A
GA
Hay
D W
DW
D000818:Animals; D016466:CHO Cells / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D004285:Dogs; D006801:Humans; D051379:Mice; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D018042:Receptors, Neurokinin-3 / Q000187:drug effects*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*
D010880:Piperidines; D011804:Quinolines; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; C106716:SB 223412; C091554:SR 142801; D002118:Calcium