MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist.
The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pKi 10.1) and potently antagonized (pKB 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies at the recombinant tachykinin NK1 (pKi 6.1) and NK3 (pKi 6.4) receptors, and at a number of 34 molecular targets including receptors, transporters and ion channels. In isolated smooth muscle preparations MEN15596 showed a marked species selectivity at the tachykinin NK2 receptor with the highest antagonist potency in guinea-pig colon, human and pig bladder (pKB 9.3, 9.2 and 8.8, respectively) whereas it was three orders of magnitude less potent in the rat and mouse urinary bladder (pKB 6.3 and 5.8, respectively). In agreement with binding experiments, MEN15596 showed low potency in blocking selective NK1 or NK3 receptor agonist-induced contractions of guinea-pig ileum preparations (pA2<or=6). In anaesthetized guinea-pigs, MEN15596 inhibited in a dose-related and persistent manner colon contractions induced by the selective tachykinin NK2 receptor agonist, [betaAla8]neurokinin A(4-10) (3 nmol/kg i.v.), either after intravenous (ED50 0.18 micromol/kg), intraduodenal (ED50 3.16 micromol/kg) or oral administration (10-30 micromol/kg) without affecting, at 3 micromol/kg, i.v., the colonic contractions produced by the NK1 receptor selective agonist [Sar9]substance P sulfone (3 nmol/kg i.v.). In addition MEN15596 was effective in inhibiting bronchoconstriction produced by i.v. administration of [betaAla8]neurokinin A(4-10). Overall the results indicate that MEN15596 is a potent and selective tachykinin NK2 receptor antagonist possessing high affinity and potency for guinea-pig, pig and human receptor, long duration of action in in vivo experiments and good oral bioavailability.
Cialdai
Cecilia
C
Pharmacology Department, Menarini Ricerche S.p.A, via Rismondo 12A, I-50131, Florence, Italy.
Tramontana
Manuela
M
Patacchini
Riccardo
R
Lecci
Alessandro
A
Catalani
Claudio
C
Catalioto
Rose-Marie
RM
Meini
Stefania
S
Valenti
Claudio
C
Altamura
Maria
M
Giuliani
Sandro
S
Maggi
Carlo Alberto
CA
D000368:Aged; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013552:Swine; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
C516535:6-methylbenzo(b)thiophene-2-carboxylic acid (1-(2-phenyl-((1-(tetrahydropyran-4-ylmethyl)piperidin-4-ylmethyl)carbamoyl)ethylcarbamoyl)cyclophenyl)amide; D004151:Dipeptides; D010446:Peptide Fragments; D018041:Receptors, Neurokinin-2; D013876:Thiophenes; C064218:neurokinin A (4-10), beta-Ala(8)-; D015288:Neurokinin A