Minaprine [3-[(beta-morpholinoethyl)amino]-4-methyl-6-phenylpyridazine dihydrochloride] is active in most animal models of depression and exhibits in vivo a dual dopaminomimetic and serotoninomimetic activity profile. In an attempt to dissociate these two effects and to characterize the responsible structural requirements, a series of 47 diversely substituted analogues of minaprine were synthesized and tested for their potential antidepressant, serotonergic, and dopaminergic activities. The structure-activity relationships show that dopaminergic and serotonergic activities can be dissociated. Serotonergic activity appears to be correlated mainly with the substituent in the 4-position of the pyridazine ring whereas the dopaminergic activity appears to be dependent on the presence, or in the formation, of a para-hydroxylated aryl ring in the 6-position of the pyridazine ring.
The synthesis of different diazonium salts derived from homo- and heterocyclic aromatic amines bearing anionic residues is described. The chemical stabilities of these compounds were established at different pH's, and the compounds were tested accordingly in binding experiments for the rat brain gamma-aminobutyric acid (GABA) receptor, for which they could ultimately be used as irreversible affinity or photoaffinity probes. The aromatic heterocyclic series studied were 2-aminoimidazole, 2-aminothiazole, and 4-aminopyridine N-oxide. The derived diazonium salts are unstable compounds at neutral pH unless they are able to be deprotonated to the corresponding diazo form. As such, the 2-diazoimidazole-4(5)-acetic acid (3b) is stable in neutral medium and recognizes the GABA receptor (IC50 = 70 microM). The homocyclic aromatic diazonium salts showed sufficient stability to be tested in binding experiments. The diazonium salts derived from m-sulfanilic acid and 8-sulfonaphthylamine were the most interesting (10b, IC50 = 10 microM; 15b, IC50 less than 100 microM). In this series, the compounds that deprotonate at neutral pH (hydroxybenzenediazonium derivatives 12b-14b) showed increased chemical stability but decreased affinity for the GABA receptor. This difference between the diazoimidazole and the diazohydroxybenzene series is attributed to a different charge distribution between the two series. The ligands 3b, 10b, and 15b can be used as potential irreversible probes for the GABA receptor.
Aminopyridazinium halides such as (VI) are prepared from the chloropyridazines (I) and their GABA receptor affinities are tested.
Na[(tert-Butoxy)carbonyl]-2-diazo-~-histidine methyl ester 1 was synthesized starting from the corresponding L-histidine derivative. The physico-chemical properties of this new photoactivatable amino-acid derivative were established. The synthetic precursor of 1,2-amino-~-histidine derivative 3, was best isolated and characterized as 2-amino-Nr-[(tert-butoxy)carbonyl]-~T-tosyl-~-histidine methyl ester (4). Selective deprotections of 4 (N"-Boc, N'-Tos, COOMe) were achieved, thus allowing the use of the corresponding products in peptide synthesis. The optically active dipeptides 8 and 9 were synthesized by coupling 2-amino-Nr-tosyl-~-histidine methyl ester ( 5 ) with N-[(tert-butoxy)cdrbonyl]-L-alanine and N'-[(rert-buto~y)carbonyl]-N~-tosyl-~-histidine (6) with L-alanine methyl ester, respectively. The question of selective diazotization of a 2-aminohistidine residue in a synthetic peptide was studied using competitive diazotizations between 2-amino-lH-imidazole and several amino-acid derivatives susceptible to undergo nitrosylation. The results show that synthetic photoactivatable peptides incorporating a 2-diazohistidine residue might become useful photoaffinity probes.Introduction. -The discovery of numerous peptides involved in the recognition and modulation of hormone or neuromediator receptors stimulated the design and the synthesis of peptide analogs in order to study ligand-receptor interactions. Among these probes, photoactivatable structures were conceived to label irreversibly the receptor at a target binding site by means of photoaffinity labelling experiments [l]. Two major results are expected from this approach, either to identify and characterize an unknown receptor or to define at a molecular level the ligand-receptor interactions.The synthesis of photoactivatable peptides was first conceived by tagging a photosensitive group to an existing peptide. Most of the described examples used electrophilic reagents bearing an arylazido or a benzophenone moiety, the coupling of the reagent to the peptide being generally directed towards the C-terminal [2] or towards nucleophilic residues existing on the peptide such as the primary amino group of a lysine side chain [3]. Besides the problem of selectivity of modification which can arise, the major limitation of this method is the consequent structural changes caused by the attachment of the photosensitive group on the natural ligand which often induces a loss in binding affinity. The design of a photosensitive amino-acid analog structurally related to a natural amino acid and which could be incorporated in the peptide during the synthesis (solid phase or in solution), would overcome the above mentioned limitations. As such, the 4'-azidophenylalanine derivative [4] has been developed and used as a substitute for phenylalanine in several peptides [5]. The syntheses of those peptides used a 4'-nitrophenylalanine precursor which was subsequently transformed to the corresponding 4'-azido derivative.
m-Sulfonate benzene diazonium chloride (MSBD) was used to affinity-label the gamma-aminobutyric acid (GABA) binding site from rat brain membranes. To assess the irreversibility of the labeling reaction, we used an efficient ligand dissociation procedure combined to a rapid [3H]muscimol binding assay, both steps being performed on filter-adsorbed membranes. Inactivation of specific [3H]-muscimol binding sites by MSBD and its prevention by GABA were both time- and concentration-dependent. The time course of MSBD labeling was shortened as the pH of the incubation medium was increased from 6.2 to 8. These data suggest that MSBD can efficiently label the GABA binding site through alkylation of a residue having an apparent dissociation constant around neutrality.
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