title: MEN 11420, a potent and selective tachykinin NK2 receptor antagonist in the guinea-pig and human colon.
abstract: We have characterized the action of the novel, water-soluble, tachykinin NK2 receptor antagonist MEN 11420 ([Asn(2-AcNH-beta-D-Glc)-Asp-Trp-Phe-Dap-Leu] c(2 beta-5 beta)) on the circular muscle of the guinea-pig and human colon in vitro and on the guinea-pig colon in vivo. In organ bath experiments on guinea-pig colon MEN 11420 produced a concentration-dependent rightward shift of the concentration-response curve to the NK2 receptor selective agonist, [beta Ala8]neurokinin A (NKA) (4-10) with a pKB value of 8.1. Up to 1 microM MEN 11420 had no effect on the concentration-response curve to methacholine, to the NK1 receptor selective agonist, [Sar9]substance P (SP) sulfone, to the NK3 receptor selective agonist, senktide, or on the response to exogenous SP. The response to exogenous NKA was inhibited, although the shift of the concentration-response curve to NKA produced by MEN 11420 at 1 microM (dose ratio 5.3) was much smaller than that produced against [beta Ala8]NKA (4-10) (dose ratio 102), presumably because NKA also stimulates NK1 receptors at relatively low concentrations. In sucrose gap, MEN 11420 concentration-dependently inhibited both depolarization (IC50 0.34 microM) and contraction (IC50 = 0.32 microM) produced by [beta Ala8]NKA (4-10) (0.3 microM for 10 s) in the guinea-pig colon without affecting the corresponding responses produced by [Sar9]SP sulfone. When similar experiments were performed in the circular muscle of the human colon MEN 11420 concentration-dependently inhibited both depolarization and contraction induced by [beta Ala8]NKA(4-10) with IC50s of 99 and 75 nM, respectively. MEN 11420 (1 microM) had no effect on the nonadrenergic noncholinergic (NANC) depolarization and contraction produced by a short period of electrical field stimulation (EFS, 10 Hz for 1 s) in the guinea-pig colon and selectively inhibited the sustained component of depolarization produced during a prolonged period of EFS (3 Hz for 3 min), without affecting the concomitant depolarization. Nifedipine (1 microM) eliminated the NANC contraction to a short period of EFS and the phasic contraction in response to a prolonged period of EFS. MEN 11420 (1 microM) abolished the nifedipine-resistant NANC contraction produced by prolonged period of electrical field stimulation (EFS, 3 Hz for 3 min). All electrical and mechanical NANC responses to EFS which were resistant to MEN 11420, either in the absence or presence of nifedipine, were abolished by the subsequent application of the NK1 receptor antagonist, SR 140333 (1 microM). Up to 3 microM, MEN 11420 had no significant effect on the cholinergic excitatory junction potential or the NANC inhibitory junction potential evoked by single pulse EFS, nor did it affect membrane conductance. In urethane-anaesthetized guinea-pigs MEN 11420 (10-100 nmol/kg i.v.) produced a dose-dependent and long lasting (> 3 h) inhibition of the contractile response (15 +/- 2 mmHg) of the proximal colon induced by [beta Ala8]NKA (4-10) (3 nmol/kg i.v.). MEN 11420 (300 nmol/kg i.v.) did not affect the contraction produced by [Sar9]SP sulfone. MEN 11420 (300 nmol/kg) produced a limited (Emax about 40% inhibition) and transient (recovery within 60 min) inhibition of the atropine- and hexamethonium-sensitive phasic contractions of the proximal colon induced by threshold distension of a colonic balloon. On the other hand, MEN 11420 (10-300 nmol/kg i.v.) produced a dose-dependent complete and prolonged (> 2 h from administration) inhibition of the atropine-resistant and hexamethonium-sensitive phasic contraction induced by suprathreshold distension of the colonic balloon. We conclude that MEN 11420 is a potent and selective tachykinin NK2 receptor antagonist devoid of significant inhibitory activity toward excitatory transmission mediated via tachykinin NK1 or muscarinic receptors. The present findings indicate that SP and NKA are likely involved in the preferential activation of NK1 and NK2 receptors during tachykininergi
authors.affiliation: Department of Pharmacology, Menarini Ricerche, Florence, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Santicioli
authors.forename: S
authors.initials: S
authors.lastname: Giuliani
authors.forename: R
authors.initials: R
authors.lastname: Patacchini
authors.forename: M
authors.initials: M
authors.lastname: Tramontana
authors.forename: M
authors.initials: M
authors.lastname: Criscuoli
authors.forename: C A
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D003106:Colon / Q000187:drug effects*; D004347:Drug Interactions; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D018041:Receptors, Neurokinin-2 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000145:classification
chemical_list: C107754:MEN 11420; D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2