Conformational rigidity versus flexibility in a novel peptidic neurokinin A receptor antagonist

Abstract

Neurokinin A receptor antagonists have been proposed as a new class of drugs for several applications in humans (asthma, 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. MEN10627 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.

MEN 11420 (Nepadutant), a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist

“…This characteristic distinctly separates this class of compounds from non‐peptide tachykinin receptor antagonists, such as SR 48968, which possesses sizeable affinity for μ opioid receptors (Martin et al , 1992; Boyle et al , 1993) and local anaesthetic‐like activity (Wang et al , 1995). It appears likely that the highly constrained backbone of MEN 10627 and MEN 11420 (Pavone et al , 1995a,b) which is optimized for interacting with NK 2 receptors, does not easily enable it to fit into other binding sites. A similar explanation may, at least in part, account for the resistance to metabolic degradation showed by MEN 10627 and, especially, MEN 11420.…”

“…In our search for potent and selective tachykinin NK 2 receptor antagonists, we speculated that a common conformational feature should be present in NK 2 receptor agonists, such as [βAla 8 ]NKA(4–10) (Saviano et al , 1991), and certain peptide‐derived antagonists, such as the cyclic hexapeptide L‐659–877 (cyclo(Leu‐Gln‐Tpr‐Phe‐Gly‐Met), Williams et al , 1988; Giolitti & Maggi, 1994). From molecular modelling studies we postulated that a β‐turn around the Trp‐Phe segment would be important for high affinity ligand‐receptor interaction: on this basis, a conformational constraint which could lock the hypothetically active conformation in the monocyclic NK 2 receptor antagonist L‐659–877 was designed (Pavone et al , 1995a,b). The resulting compound, MEN 10627 (cyclo(Met‐Asp‐Trp‐Phe‐Dap‐Leu)cyclo(2β‐5β)), bears a lactam bridge between the side chains of two amino acids and presents, therefore, a bicyclic structure which contains two consecutive β‐turns (Maggi et al , 1994; Pavone et al , 1995a,b).…”

“…From molecular modelling studies we postulated that a β‐turn around the Trp‐Phe segment would be important for high affinity ligand‐receptor interaction: on this basis, a conformational constraint which could lock the hypothetically active conformation in the monocyclic NK 2 receptor antagonist L‐659–877 was designed (Pavone et al , 1995a,b). The resulting compound, MEN 10627 (cyclo(Met‐Asp‐Trp‐Phe‐Dap‐Leu)cyclo(2β‐5β)), bears a lactam bridge between the side chains of two amino acids and presents, therefore, a bicyclic structure which contains two consecutive β‐turns (Maggi et al , 1994; Pavone et al , 1995a,b).…”

Large-scale production of peptides using the solid-phase continuous flow method. Preparative synthesis of the novel tachykinin antagonist MEN 10627

“…More recently, a continuous flow methodology was applied [7] to the semi-large-scale synthesis of Leu 5 -enkephalin (pen-tapeptide) and human angiotensin I (decapeptide), resulting in an efficient process giving good yields of the final purified peptides. In this paper we describe the large-scale synthesis of the novel bicyclic hexapeptide MEN 10627, a highly selective Neurokinin A receptor antagonist, endowed with remarkable potency and long duration of action in vivo [8][9][10], currently in the pre-clinical phase and aiming at clinical evaluation.…”

The crystal structure of Afc-containing peptides

“…[11][12][13][14] In particular, the incorporation of C ␣,␣ -disubstituted amino acids into bioactive peptides provides an excellent tool to confer conformational rigidity, [15][16][17][18][19][20] which is well known to be an essential requirement to increase potency and selectivity, to improve bioavailability, and to enhance the resistance to peptidases. 21,22 In the last few years we devoted our attention to the conformational behavior of new C ␣,␣ -dialkylated residues, containing different groups of increasing bulkiness on the C ␣ atom. [23][24][25][26][27][28] In particular, the conformational preferences of Dg (C ␣,␣ -diphenylglycine) containing peptides have been recently analyzed.…”