ABSTRACT
By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.
Subject(s)
Cholinesterase Inhibitors/metabolism , Pyridazines/metabolism , Receptors, G-Protein-Coupled/metabolism , Acetylcholinesterase/drug effects , Animals , Butyrylcholinesterase/drug effects , Dogs , Humans , Ligands , Madin Darby Canine Kidney CellsABSTRACT
The synthesis of three series of novel 4-alkyl-5-(5'-chlorothiophen-2'-yl)-pyrazole-3-carbamoyl analogues of rimonabant with affinity for the CB1 cannabinoid receptor subtype is reported. Amongst the novel derivatives, compounds 21j, 22a, 22c, and 22f showed affinity values expressed as Ki ranging from 5.5 to 9.0 nM. Derivative 23e revealed a good CB1 affinity (K(i) = 11.7 nM) and the highest CB1 selectivity of the whole series (K(i)CB2/K(i)CB1 = 384.6). These new compounds appeared to be able to pass the blood brain barrier and to counteract the activity of cannabinoid agonist. According to the results of mice vas deferens assays, as in the case of rimonabant, derivatives 21a, 22a, and 22b showed inverse agonist activity. In contrast, as a preliminary result to be confirmed, compound 23a exhibited neutral antagonist profile. According to the data obtained through an acute animal model, selected compounds 21a, 22a, and 23a evidenced the capability to significantly reduce food intake. At specific conditions, the effect of the novel compounds were higher than that induced by rimonabant. Amongst the novel CB1 antagonist compounds, 23a may represent a useful candidate agent for the treatment of obesity and its metabolic complications, with reduced side effects relative to those instead observed with rimonabant.
Subject(s)
Appetite Depressants/chemical synthesis , Cannabinoid Receptor Antagonists/chemical synthesis , Eating/drug effects , Piperidines/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Appetite Depressants/pharmacology , Blood-Brain Barrier , Body Temperature/drug effects , Cannabinoid Receptor Antagonists/pharmacology , Drug Evaluation, Preclinical , Gastrointestinal Transit/drug effects , Male , Mice , Molecular Structure , Obesity/drug therapy , Pyrazoles/chemistry , Receptor, Cannabinoid, CB1/agonists , Rimonabant , Structure-Activity Relationship , Vas Deferens/drug effectsABSTRACT
Designed as a new group of tricyclic molecules containing the thienocycloheptapyridazinone ring system, a number of 2N-substituted-hexahydrothienocycloheptapyridazinone derivatives were synthesized and their biological activity evaluated. Among the synthesized compounds, derivatives 7d and 7h were found to possess cytotoxic activity against non-small cell lung cancer and central nervous system cancer cell lines, respectively.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , HumansABSTRACT
Alpha series of novel 3,6-diazabicyclo[3.1.1]heptane derivatives 4a-f was synthesized and their affinity and selectivity towards alpha4beta2 and alpha7 nAChR subtypes were evaluated. The results of the current study revealed a number of compounds (4a, 4b and 4c) having a very high affinity for alpha4beta2 (K(i) at alpha4beta2 ranging from 0.023 to 0.056 nM) versus alpha7 nAChR subtypes; among these compounds, the 3-(6-bromopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane 4c was found to be the most alpha7alpha4beta2 selective term in receptor binding assays (alpha7alpha4beta2=1295). Moreover, compound 4d also had high affinity for the alpha4beta2 nAChR subtype (K(i)=1.2 nM) with considerably high selectivity (alpha7/alpha4beta2=23300).
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Heptanes/chemical synthesis , Heptanes/pharmacology , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Binding Sites , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Heptanes/chemistry , Ligands , Molecular Structure , Nicotine/metabolism , Nicotinic Agonists/chemistry , Structure-Activity RelationshipABSTRACT
New analogues (2a-p) of the previously reported CB(2) ligands 6-methyl- and 6-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamides (1a,b) have been synthesized and evaluated for cannabinoid receptor affinity. One example, 1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexyilamine-1,4-dihydroindeno[1,2-c] pyrazole-3-carboxamide (2a) was shown to have single digit nanomolar affinity for cannabinoid CB(2) receptors. Furthermore, compounds 2a and 2b, as well as lead structures 1a,b, were also shown to be agonist in an in vitro model based on human promyelocytic leukemia HL-60 cells.
