ABSTRACT
A new method for solid phase parallel synthesis of chemically and conformationally diverse macrocyclic peptidomimetics is reported. A key feature of the method is access to broad chemical and conformational diversity. Synthesis and mechanistic studies on the macrocyclization step are reported.
Subject(s)
Chemistry, Pharmaceutical/methods , Peptides, Cyclic/chemistry , Combinatorial Chemistry Techniques , Dimerization , Dipeptides , Models, Chemical , Models, Molecular , Molecular Conformation , Molecular Mimicry , Molecular Structure , Peptides/chemistry , Silver/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Rigidified derivatives have been designed and synthesized assuming the g+t conformer of acetylcholine (N-C-C-O=+60 degrees, C-C-O-C=180 degrees ) as active conformation for binding to cytisine sensitive neuronal nicotinic receptors. The SAR of the compounds evaluated, along with those of more flexible analogues, support the g+t conformer hypothesis and highlight the stringent steric limitation of this nicotinic receptor sub-type. Compound 3e has low microM affinity for cytisine sensitive nicotinic receptor binding sites while being selective with regard to the alpha-bungarotoxin sensitive subclass. We also report few compounds with microM affinity for the alpha-bungarotoxin sensitive subclass.
Subject(s)
Acetylcholine/chemistry , Neurons/metabolism , Receptors, Nicotinic/drug effects , Acetylcholine/metabolism , Alkaloids/pharmacology , Animals , Azocines/pharmacology , Bungarotoxins/pharmacology , Drug Design , Gas Chromatography-Mass Spectrometry , In Vitro Techniques , Indicators and Reagents , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Molecular Mimicry , Neurons/drug effects , Prosencephalon/drug effects , Prosencephalon/metabolism , Quinolizines/pharmacology , Radioligand Assay , Rats , Structure-Activity RelationshipABSTRACT
The caffeine metabolite 5-acetamido-6-formylamino-3-methyluracil (AFMU) and its product of spontaneous deformylation 5-acetamido-6-amino-3-methyluracil (AAMU) were synthesized. Their ultraviolet absorption spectra differed significantly from each other and wavelengths of absorption maximum and molar extinction coefficients varied with pH. The changes of the absorption spectrum parameters of AFMU and AAMU with pH indicated that they ionized with pK(a) of 5.7 and 8.3, respectively. The spontaneous deformylation of AFMU in solutions of different pH and urine were investigated spectrophotometrically and by high-performance liquid chromatography. The data showed the following: (a) AFMU transformed uniquely to AAMU; (b) deformylation obeyed first-order kinetics under the different conditions tested; (c) the half-life of AFMU varied between 7.8 and 36 h between pH 9.0 and 2.0 at 24 degrees C, with a maximum of 150 h at pH 3.0; (d) AFMU deformylated below pH 2.0 and above pH 10.0 with a half-life of less than 4.6 h; (e) half-lives of AFMU in urine were 57 and 12.5 h at 24 and 37 degrees C, respectively, comparable to those in buffers at equivalent pH and temperature. The results are discussed in relation to the mechanism of deformylation and the use of caffeine as a probe drug for NAT2 phenotyping.
