ABSTRACT
Analogues of [Orn6]-SP6-11 have been synthesized in which the Met11-NH2 residue is replaced by the alpha, gamma-dimethyl, alpha, gamma-dibenzyl and alpha, gamma-di-tert-butyl esters of glutamic acid. These analogues were tested in three in vitro preparations representative of NK-1, NK-2 and NK-3 receptor types for agonist and antagonist activity. The dimethyl analogue is a selective full agonist in the NK-1 receptor type and a weak antagonist in the other two receptor types, while the dibenzyl and the di-tert-butyl analogues are potent antagonists in the NK-1 receptor type and weak antagonists in the other two receptor types. It is concluded that appropriate modification at the alpha-carboxamide and the side chain of the methionine residue of substance P may induce antagonism without using D-amino acids.
Subject(s)
Amino Acids/chemistry , Glutamates/chemistry , Methionine/chemistry , Oligopeptides/chemical synthesis , Substance P/analogs & derivatives , Substance P/antagonists & inhibitors , Amino Acid Sequence , Animals , Colon/drug effects , Glutamic Acid , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Molecular Sequence Data , Oligopeptides/pharmacology , Peptide Fragments/pharmacology , Portal Vein/drug effects , Rats , Receptors, Neurotransmitter/drug effects , Receptors, Tachykinin , Structure-Activity Relationship , Substance P/pharmacologyABSTRACT
Mixed carboxylic-phosphinic anhydrides derived from peptide acids and 1-oxo-1-chlorophospholane have been applied in the synthesis of the protected [Leu11]-SP by the fragment coupling strategy. The yields from fragment couplings were ca. 75%, the products were of high purity while the conditions of formation and coupling of the corresponding mixed phosphinic anhydrides, for optimum yields, have been evaluated.
Subject(s)
Substance P/chemistry , Amino Acid Sequence , Anhydrides/chemistry , Carboxylic Acids/chemistry , Molecular Sequence Data , Phosphinic Acids/chemistryABSTRACT
Analogues of [Orn6]-SP6-11 have been synthesized in which the Met11 residue is replaced by glutamate gamma-alkylesters. These analogues were tested in three in vitro preparations representative of NK-1, NK-2, and NK-3 receptor types. Substitution of the SCH3 group of the Met11 side chain by a COOR (R = methyl, ethyl, n-propyl, n-butyl, cyclohexyl) group results in analogues which are full agonists in NK-1 and NK-2 preparations but show little agonist activity in the NK-3 preparation. When the SCH3 group is replaced by a t-butyl ester group and the resulting analogue is a full agonist in all the above preparations and more active than the parent hexapeptide and SP-OCH3 at NK-1 receptors. It is concluded that for activity at NK-1 receptors methionine can be replaced by gamma-t-butyl glutamate without loss of activity, whilst at NK-2 and NK-3 receptors the above substitution increases the activity of [Orn6]-SP6-11. Other gamma-alkyl esters of the glutamic acid reduce its biological activity.