ABSTRACT
Compound 1 obtained by random screening and displaying a micromolar activity on the mu opiate receptor was chosen as a starting point for optimization. Two complementary concepts of similarity were used for the design of analogues and compared. These are based, respectively, on a computer-aided comparison of pharmacophoric patterns and on topological similarity. The structure-activity relationships are discussed in light of both similarity concepts. Compound 40, an N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl)acetamide derivative, designed by combining the structure-activity relationships enlightened by each method, has a subnanomolar affinity for mu (h) receptor (IC(50) = 0.9 nM). It is a promising lead, allowing the design of a new series of analogues substituted at the N-3 of the spirocycle moiety.
Subject(s)
Imidazoles/chemical synthesis , Receptors, Opioid, mu/metabolism , Spiro Compounds/chemical synthesis , Animals , Cerebral Cortex/metabolism , Combinatorial Chemistry Techniques , Humans , Imidazoles/chemistry , Imidazoles/metabolism , In Vitro Techniques , Ligands , Magnetic Resonance Spectroscopy , Radioligand Assay , Rats , Receptors, Opioid, mu/chemistry , Solubility , Spiro Compounds/chemistry , Spiro Compounds/metabolism , Structure-Activity RelationshipABSTRACT
Two compounds, obtained by random screening, and displaying micromolar activities on the mu opiate receptor were used as starting points for optimization. In that work, the traditional concept of the activity of a compound (related to one or a few targets) was extended to the comprehensive pharmacological profile of that compound on more than 70 receptors, transporters, and channels relevant to a CNS-oriented project. Using the two complementary design strategies based on two similarity concepts described in the previous paper, we have obtained analogues with IC(50) values ranging between 0.9 nM and a few micromolar on the mu receptor and displaying qualitatively different profiles. We discuss here, both on a case-by-case basis and from a statistical standpoint, the pharmacological profiles in light of the two similarity concepts.
Subject(s)
Combinatorial Chemistry Techniques , Ligands , Structure-Activity Relationship , Brain/metabolism , Carrier Proteins/metabolism , Data Interpretation, Statistical , In Vitro Techniques , Ion Channels/metabolism , Models, Molecular , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/metabolism , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/metabolism , Radioligand Assay , Receptors, Cell Surface/metabolismSubject(s)
Infant Mortality , Morbidity , Mortality , Child , Child, Preschool , Congo , Female , Humans , Infant , Infant, Newborn , MaleABSTRACT
Solution-phase synthesis and evaluation of a library of 31 sulfonamides as inhibitors of a chloroquine-resistant strain of Plasmodium falciparum are described. The most potent compound displayed an activity 100-fold better than chloroquine. Experiments using a fluorescent sulfonamide derivative suggest that their site of action inside the parasite is different to that of chloroquine.