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M B Giles

Publications and source records attributed to M B Giles.

12 recordsLinked to original sources
PubMed1983

Divergent structure activity relationships in series of enkephalin agonists and cognate antagonists.

Diallylation of the amino group of [Leu]enkephalin methyl ester yields a moderately potent, delta-selective opiate receptor antagonist. The diallyl congeners of a larger range of potent mu-and delta-selective enkephalin agonists have been prepared and were found to be weak, non-selective antagonists as assessed by their ability to antagonise the effects of normorphine and [Leu]enkephalin on the field-stimulated mouse vas deferens. Conversely, whereas [Gly3 psi (CH2S)Phe4,Leu5]enkephalin and [Gly3 psi(CH2S)-D-Phe4,Leu5]enkephalin are virtually inactive as opiate agonists the corresponding diallyl analogues are moderately potent, highly selective delta-antagonists. Analogues of diallyl[Leu]enkephalin in which the Gly2 and Gly3 residues have been replaced by D- and L- Ala have also been prepared and tested as delta-receptor antagonists. In addition, the empiric energy program ECEPP has been used to derive eighteen low energy conformations of diallyl[Leu]enkephalin and to estimate the effect of the D- and L-Ala substitutions on the conformer energies. Two conformers were identified for which there was a partial correlation between the variations in conformational energy and delta-antagonist potency.

Animals↗
PubMed1978

Synthesis and biological activity of highly active alpha-aza analogues of luliberin.

Analogues of luliberin containing an alpha-azaamino acid in position 6, 9, or 10 (I--XIV) have been synthesized by the solution method of peptide synthesis. Two nonaza analogues, [D-Phe6]- and [D-Ser(But)6,des-Gly-NH2(10),Pro-ethylamide9]luliberin, were also synthesized for comparison. The ovulation-inducing activity of the compounds was evaluated in androgen-sterilized constant-estrus rats. A combination of D-amino acid replacement in position 6 with an azaglycine residue at position 10 resulted in highly active compounds which were superior to the corresponding nonaza analogues. The most active compoungs, [D-Phe6,Azgly10-a1-, [D-Tyr(Me)6,Azgly10]-, and [D-Ser(But)6,Azgly10]luliberin, were about 100 times as potent as luliberin. N-Methylleucine substitution in position 7 in these compounds resulted in decreased activity; [D-Phe6,MeLeu7,Azgly10]- and [D-Tyr(Me)6,MeLeu7,Azgly10]luliberin were only 50 times as active as luliberin. The presence of either an azaproline residue in position 9, an azaphenylalanine or azaglycine residue in positions 6 and 10, or a tert-butyl ether protecting group on the hydroxyl group of the tyrosine residue in position 5 resulted in compounds with significantly reduced biological activity.

Amino Acid Sequence↗
PubMed1976

Synthesis and biological activity of alpha-azapeptides: alpha-aza-analogues of luteinizing hormone releasing hormone.

The term "alpha-azapeptides" is applied to analogues derived by change of one or more of the alpha-CHs of amino-acid residues in peptides by N; in such analogues the overall polarity of the molecule and the spacing of side-chain residues is preserved, but stability towards peptidases may be increased because of the changed conformational situation at the residue or residues involved in the change. Three alpha-aza-analogues of LHRH, i.e. azaglycine6-, azalanine6-, and azaglycine10-LHRH, and two alpha-aza-analogues, of des-His-LHRH, i.e. azaglycine6- and azalanine3-des-His-LHRH, were prepared. The three alpha-aza-analogues of LHRH were as active as LHRH in inducing ovulation in androgen-sterilized, constant-oestrus rats, but less potent than LHRH in causing LH release in immature male rats. Evidence of increased duration of action was not obtained. The two aza-analogues of des-His-LHRH were neither agonists nor antagonists in these two test systems.

Amino Acid Sequence↗