A REVIEW OF THE DESIGN, SYNTHESIS AND BIOLOGICAL-ACTIVITY OF THE BICYCLIC HEXAPEPTIDE TACHYKININ NK2 ANTAGONIST MEN-10627

We review the reported 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)c yclo(2 beta-5 beta). MEN 10,627 possesses a highly constrained structu re characterized by two consecutive beta-turns, as confirmed by the al most coincident results of NMR and X-ray analyses. The compound has be en efficiently synthesized by solid-phase methodology using either Boc or Fmoc strategies, It is quite stable to metabolic degradation and i s endowed with high affinity and selectivity for NK2 receptor expresse d in various species. At the hamster NK2 receptor MEN 10,627 is about 30-fold more potent than the nonpeptide NK2 receptor antagonist, SR 48 ,968, while the converse is true for the rabbit NK2 receptor. MEN 10,6 27 and SR 48,968 show comparable affinities for the human NK2 receptor . MEN 10,627 produces a long lasting inhibition of the response to the selective NK2 receptor agonist [beta Ala(8)]NKA(4-10) in the rat urin ary bladder in vivo after intravenous, intranasal and intraduodenal ad ministration. Therefore different administration routes are possible f or this compound that overcomes the usual drawbacks for the applicatio n of peptides as drugs.