ABSTRACT
The aggregation of amyloid ß (Aß) peptides and deposition of amyloid plaques are implicated in the pathogenesis of Alzheimer's disease (AD). Therefore, blocking Aß aggregation with small molecules has been proposed as one therapeutic approach for AD. In the present study, a series of ranitidine analogs containing cyclic imide isosteres were synthesized and their inhibitory activities toward Aß aggregation were evaluated using in vitro thioflavin T assays. The structure-activity relationship revealed that the 1,8-naphthalimide moiety provided profound inhibition of Aß aggregation and structural modifications on the other parts of the parent molecule (compound 6) maintained similar efficacy. Some of these ranitidine analogs also possessed potent inhibitory activities of acetylcholinesterase (AChE), which is another therapeutic target in AD. These ranitidine analogs, by addressing both Aß aggregation and AChE, offer insight into the key chemical features of a new type of multi-target directed ligands for the pharmaceutical treatment of AD.
Subject(s)
Alzheimer Disease/drug therapy , Drug Design , Ranitidine/chemical synthesis , Ranitidine/therapeutic use , Amyloid beta-Peptides/metabolism , Animals , Cattle , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Imides/chemistry , Ligands , Protein Aggregates/drug effects , Ranitidine/chemistryABSTRACT
Using molecular modeling and rationally designed structural modifications, the multi-target structure-activity relationship for a series of ranitidine analogs has been investigated. Incorporation of a variety of isosteric groups indicated that appropriate aromatic moieties provide optimal interactions with the hydrophobic and π-π interactions with the peripheral anionic site of the AChE active site. The SAR of a series of cyclic imides demonstrated that AChE inhibition is increased by additional aromatic rings, where 1,8-naphthalimide derivatives were the most potent analogs and other key determinants were revealed. In addition to improving AChE activity and chemical stability, structural modifications allowed determination of binding affinities and selectivities for M1-M4 receptors and butyrylcholinesterase (BuChE). These results as a whole indicate that the 4-nitropyridazine moiety of the JWS-USC-75IX parent ranitidine compound (JWS) can be replaced with other chemotypes while retaining effective AChE inhibition. These studies allowed investigation into multitargeted binding to key receptors and warrant further investigation into 1,8-naphthalimide ranitidine derivatives for the treatment of Alzheimer's disease.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Nootropic Agents/chemistry , Nootropic Agents/pharmacology , Ranitidine/analogs & derivatives , Ranitidine/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Alzheimer Disease/metabolism , Animals , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Humans , Mice , Models, Molecular , Naphthalimides/chemical synthesis , Naphthalimides/chemistry , Naphthalimides/pharmacology , Nootropic Agents/chemical synthesis , Ranitidine/chemical synthesis , Receptor, Muscarinic M1/metabolism , Receptor, Muscarinic M4/metabolism , Structure-Activity RelationshipABSTRACT
The H(2) antagonists, ranitidine and famotidine, exhibit saturable absorptive transport across Caco-2 cell monolayers and human intestine via a yet unidentified mechanism. A photoreactive derivative of famotidine has been synthesized and evaluated as a photoaffinity probe for the putative transporter protein(s). The probe irreversibly inhibited ranitidine transport across Caco-2 cell monolayers and irreversibly increased the transepithelial electrical resistance (TEER) after UV activation. Photoaffinity labeling was protected by a molar excess of famotidine.
Subject(s)
Famotidine/analogs & derivatives , Famotidine/chemical synthesis , Histamine H2 Antagonists/chemical synthesis , Photoaffinity Labels/chemical synthesis , Ranitidine/analogs & derivatives , Ranitidine/chemical synthesis , Biological Transport , Caco-2 Cells , Carrier Proteins/metabolism , Electric Conductivity , Famotidine/pharmacokinetics , Histamine H2 Antagonists/pharmacokinetics , Humans , Photoaffinity Labels/pharmacokinetics , Ranitidine/pharmacokinetics , Ultraviolet RaysABSTRACT
An improved synthesis of the antiulcer drug Ranitidine from an oxazolidine derivative is reported.
Subject(s)
Chemistry, Pharmaceutical/methods , Ranitidine/chemical synthesis , Ranitidine/chemistry , Technology, Pharmaceutical/methodsABSTRACT
Pyridyl and 1,6-dihydropyridyl ranitidine analogues 1 and 2 were obtained by applying an improved modification of ranitidine synthesis. Compound 1 shows a selective H2 antagonistic activity while compound 2 is a non-selective histamine antagonist.
Subject(s)
Histamine H1 Antagonists/chemical synthesis , Histamine H2 Antagonists/chemical synthesis , Ranitidine/analogs & derivatives , Animals , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Guinea Pigs , Heart Rate/drug effects , Histamine H1 Antagonists/pharmacology , Histamine H2 Antagonists/pharmacology , In Vitro Techniques , Male , Mice , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Ranitidine/chemical synthesis , Ranitidine/pharmacologyABSTRACT
Clenbuterol, a beta antagonist, and ranitidine, a histamine-receptor antagonist, were associated with contact dermatitis in a chemist. The allergen in the former was an intermediate in the synthesis called beta. In the latter, intermediates and the finished base and hydrochloride were responsible.
Subject(s)
Clenbuterol/adverse effects , Dermatitis, Contact/etiology , Dermatitis, Occupational/chemically induced , Ethanolamines/adverse effects , Ranitidine/adverse effects , Adult , Clenbuterol/chemical synthesis , Humans , Male , Patch Tests , Ranitidine/chemical synthesisABSTRACT
Allergic contact sensitivity to 5-[(2-aminoethyl)thiomethyl]-N, N-dimethyl-2-furanmethanamine, a diamino intermediate in the synthesis of a novel H2 antagonist, Ranitidine is reported in an industrial chemist with hand dermatitis, who had been working for a prolonged period on the conversion of this intermediate to its fumarate salt.
