First Evaluation of [11C]R116301 as an In Vivo Tracer of NK1 Receptors in Man

PURPOSE: NK1 receptors have been implicated in various neuropsychiatric and other disorders. R116301 is a selective NK1 receptor antagonist. In this pilot study, [(11)C]R116301 was evaluated as a potential positron emission tomography (PET) ligand for the NK1 receptor. PROCEDURES: Two dynamic PET studies were performed in three normal volunteers before and after a blocking dose of aprepitant. Data were analyzed using striatum to cerebellum standardized uptake value (SUV) ratios. RESULTS: Baseline SUV ratios at 60-90 min after injection ranged from 1.22 to 1.70. Following aprepitant administration, this specific signal was completely blocked. Aprepitant administration did not significantly affect uptake in cerebellum, confirming the absence of NK1 receptors in cerebellum. CONCLUSION: These preliminary results indicate that [(11)C]R116301 has potential as a radioligand for in vivo assessment of NK1 receptors in the human brai

Preparation of cyclic peptide tachykinin antagonists.

Compounds prepared via cyclization using PyBOP/DIEA in DMF, at 10 mM gave 100% inhibition of response to substance P Me ester by isolated guinea pig ileum

A New Potent and High Selective, Long Lasting, Peptide Based Neurokinin A Antagonist: Rational Design of MEN10627

MEN 10627 is the prototype of a new class of cyclic peptide-based NK-2 receptor antagonists. Owing to its high potency and long lasting activity in vivo, MEN 10627 and its analogs are suitable candidates for clinical testing in humans

Conformational Rigidity Versus Flexibility in a Novel Peptidic Neurokinin A Receptor Antagonist

Neurokinin A receptor antagonists have been proposed as a new class of drugs for several applications in humans (asthama, intestinal motility, etc.). The rational design, synthesis, structural characterization and biological activity evaluation of a new potent, highly selective, long-lasting, peptide-based receptor antagonist are reported. The structure–activity relationship indicates that the conformational rigidity determines potency, specificity and especially the long life of the molecule in the living body. MEN 10627 is the prototype of a new class of cyclic, peptide-based, neurokinin A receptor antagonists and it is a suitable candidate for clinical testing in humans

A Novel Rigid β-Turn Molecular Scaffold

We describe here the solution 1H NMR analysis, restrained and unrestrained molecular dynamic simulations of the bicyclic peptide cyclo(Met1-asp2-Trp3-Phe4-dap5-Leu6)cyclo(2β-5β) (MEN10701) (dap:  (2R)-2,3-diaminopropionic acid). This compound is an analogue of cyclo(Met1-Asp2-Trp3-Phe4-Dap5-Leu6)cyclo(2β-5β) (MEN10627) (Dap:  (2S)-2,3-diaminopropionic acid), which is the most potent and selective, peptide-based NK2 receptor antagonist known to date. MEN10701 differs from MEN10627 for the d chirality of the Asp2 and Dap5 residues; it was designed to better understand the role of the lactame bridge in determining the shape of the molecule and to elucidate whether its position, above or below the plane containing the pharmacophores (Met1, Trp3, Phe4, and Leu6 side chains), could modulate the biological response. Despite our expectations, the uncoercible bicyclic structure of MEN10627 is dramatically coerced into a novel conformation, by the replacement of the lactame bridge forming units (Asp2 and Dap5) with residues of opposite chirality. The overall shape of MEN10701 is also quite unique because of its compactness. It is ellipsoidal instead of being rectangle-like, and the structure is stabilized by two intramolecular hydrogen bonds encompassing two type I‘ β-turns. This structure can be added to the repertoire of rigid β-turn scaffolds for the design of bioactive molecules, which require turned motifs to elicit potency and specificity

A Review of the Design, Synthesis and Biological Activity of the Bicyclic Hexapeptide Tachykinin NK2 antagonist MEN 10627

This paper reports data on the design, the conformational features and the pharmacological properties of the bicyclic peptide tachykinin NK2 receptor antagonist MEN 10,627 or cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta). MEN 10,627 possesses a highly constrained structure characterized by two consecutive beta-turns, as confirmed by the almost coincident results of NMR and X-ray analyses. The compound has been efficiently synthesized by solid-phase methodology using either Boc or Fmoc strategies. It is quite stable to metabolic degradation and is endowed with high affinity and selectivity for NK2 receptor expressed in various species