High impact information on MEN 10627

• Consistent with this, either an NK(1)-specific antagonist (GR-82334; 10(-7) M) or an NK(2)-specific antagonist (MEN 10,627; 10(-7) M) blocked responses to SP (10(-6) M) [1].
• 7. It is further concluded that MEN 10,627 exerts a selective NK2-receptor antagonism, and may be a valuable tool for assessing the functional role of NK2-receptors in gastrointestinal physiology [2].
• 1. The pharmacological profile was studied of MEN 11420, or cyclo[[Asn(beta-D-GlcNAc)-Asp-Trp-Phe-Dap-Leu]cyclo(2beta-5beta )], a glycosylated derivative of the potent, selective, conformationally-constrained tachykinin NK2 receptor antagonist MEN 10627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2beta-5beta)) [3].
• However, the vasoconstrictor action of NKA was blocked only when the preparations were exposed to a combination of NK1, NK2 and NK3 receptor antagonists (SR-140,333, MEN-10,627, PD-161,182) [4].
• As an NK2 receptor antagonist, MEN 10,627 is 10- to 100-fold more potent than the monocyclic peptide antagonist L 659,877 or cyclo(Met-Gln-Trp-Phe-Gly-Leu) [5].

Biological context of MEN 10627

• MEN 11420 (1.1 micromol/kg i.v.) showed a longer plasma half-life and a greater area under the plasma concentration-time curve value (AUC) than those of MEN 10627 [6].
• When given during ongoing acid back-diffusion, MEN 10,627 significantly enhanced the acid-evoked vasodilatation as compared with vehicle or SR 140,333 [7].
• The selective tachykinin NK2 receptor antagonist, MEN 10627 (0.01-1 microM), likewise produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. (IC50 = 0.07 microM) and contraction (IC50 = 0.03 microM) [8].
• Capsaicin (10 microM for 10-15 min) also evoked a transient increase in the frequency and half-amplitude duration of the ureteric action potentials, in a manner blocked by MEN 10,627 (3 microM), which was followed by a long period of membrane potential quiescence [9].

Anatomical context of MEN 10627

• MEN 10,627 is endowed with high affinity for NK2 receptor expressed in various species with pKB values ranging between 10.1 (hamster trachea) and 8.1 (rabbit pulmonary artery) [5].
• Different mechanism of tachykinin NK2 receptor blockade by SR 48968 and MEN 10,627 in the guinea-pig isolated gallbladder and colon [10].
• Spasmolytic effect of the NK2-receptor-selective antagonist MEN 10,627 in rat small intestine [11].
• The co-administration of SR 140,333 and MEN 10,627 nearly abolished the NANC contraction to EFS in the ileum [12].
• The co-administration of SR 140,333 and MEN 10,627 produced a profound inhibition of the response to EFS in the duodenum, larger than that produced by each antagonist alone; a fraction (about 25% of the response at 30 Hz) of the NANC contraction of the duodenum persisted in the presence of the two antagonists [12].

Associations of MEN 10627 with other chemical compounds

• In conclusion, MEN 10,627 is a potent and selective NK2 receptor antagonist, endowed with high potency and long duration of action in vivo, which is not restricted to parenteral administration.(ABSTRACT TRUNCATED AT 400 WORDS)[5]
• Contractions induced by transmural nerve stimulation and tachykinin receptor agonists selective for NK1, NK2 and NK3 receptors were used in combination with a neurokinin (NK)2 receptor antagonist, MEN 10,627, and atropine as a muscarinic receptor antagonist [13].
• The co-administration of SR 140,333 and MEN 10,627 nearly abolished the nifedipine-resistant response in the ileum while a small fraction (about 20% of control) of the response persisted in the duodenum [12].
• Pretreatment with the nicotinic antagonist hexamethonium did not change the response in any of the parameters investigated, whereas the NK2-receptor antagonist MEN 10,627 effectively inhibited all responses to NKA [14].

Gene context of MEN 10627

• On the other hand, MEN 10,627 (30-100 nmol/kg i.v.) and SR 48968 (100-300 nmol/kg i.v.) but not SR 48965 (300 nmol/kg i.v.) antagonized, at a comparable extent, duodenal contractions induced by both the selective NK2 and NK1 receptor agonists [15].
• This increased response was fully antagonized by MEN-10627, a NK2 and NK3 receptor antagonist depending on the dose [16].
• The NK2 receptor antagonist MEN 10627 which, when administered alone, had only a partial inhibitory effect on the amplitude of NANC twitches, concentration-dependently (10 nM-1 microM) inhibited the potentiating effect of CGRP [17].
• Similarly, MEN 10627 (pA2 9.20) is more active than R 396 (pA2 6.21), suggesting that the mouse NK2 receptor is similar to that of the rabbit [18].
• By examining the effects of selective agonists and antagonists for tachykinin neurokinin (NK)1, NK2 and NK3 receptors it was found that the vasculature contained only NK2 receptors that were activated by the NK2 receptor agonist [betaAla8]-NKA-(4-10) and inhibited by the NK2 receptor antagonists MEN-10,627 and GR-94,800 [4].

References