ABSTRACT
A new series of monocyclic pseudopeptide tachykinin NK-2 receptor antagonists has been derived from the lead compound MEN11558. A synthesis for these molecules sharing the same intermediate was designed and performed. The replacement of the succinic moiety with an aspartic acid and the functionalization of its amino group with a wide variety of substituents led to very potent and selective NK-2 antagonists. Best results were obtained through the insertion in position 12 of an amino group with R configuration, linked by a short spacer to a saturated nitrogen heterocycle (morpholine, piperidine, or piperazine). The study led to compounds 54 and 57, endowed with high in vivo potency at very low doses and long duration of action in animal models of bronchoconstriction. In particular 54 and 57 completely inhibited NK-2 agonist induced bronchoconstriction in guinea pig after intratracheal administration at subnanomolar doses (ED(50) = 0.27 nmol/kg and 0.15 nmol/kg, respectively).
Subject(s)
Bronchodilator Agents/chemical synthesis , Peptides, Cyclic/chemical synthesis , Receptors, Neurokinin-2/antagonists & inhibitors , Animals , Aspartic Acid , Bronchoconstriction/drug effects , Bronchodilator Agents/pharmacology , Guinea Pigs , Humans , Male , Peptides, Cyclic/pharmacology , Structure-Activity RelationshipABSTRACT
Enantiopure cycloadducts between glycals and alkyl or aryl heterodienes were selected as small, rigid, nonpeptide molecules able to superimpose to the structure of the cyclopeptide tachykinin NK-2 antagonist 1. The presence of three aromatic groups in the pyranose ring resulted essential for NK-2 affinity, while an increase in activity was shown by the corresponding sulfoxides.
Subject(s)
Monosaccharides/chemical synthesis , Oligopeptides/chemical synthesis , Receptors, Neurokinin-2/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Drug Design , Humans , Ligands , Models, Molecular , Molecular Mimicry , Monosaccharides/chemistry , Monosaccharides/pharmacology , Oligopeptides/pharmacology , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Structure-Activity Relationship , Sulfides , Sulfones , TransfectionABSTRACT
A series of cyclic pseudopeptides were synthesized containing the sequence -Trp-Phe-(D)-PhePsiCH2NH-, the terminal ends of which were bound to 2-carboxy succinate or enantiomerically enriched tricarballylic acid to give the final cyclic structures. These two molecules and their subsequent derivatives were screened for h-NK2 receptor binding and functional antagonist activity on the rabbit urinary bladder.
