ABSTRACT
The synthesis and SAR studies about the bicyclic amine, carbamate linker and aromatic ring of a 1,4-diazabicyclo[3.2.2]nonane phenyl carbamate series of alpha7 nAChR agonists is described. The development of the medicinal chemistry strategy and SAR which led to the identification of 5 and 7aa as subtype selective, high affinity alpha7 agonists as excellent leads for further evaluation is discussed, along with key physicochemical and pharmacokinetic data highlighting their lead potential.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Carbamates/chemical synthesis , Nicotinic Agonists/chemical synthesis , Phenylcarbamates/chemical synthesis , Receptors, Nicotinic/chemistry , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Carbamates/chemistry , Carbamates/pharmacokinetics , Cell Line , Humans , Male , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacokinetics , Phenylcarbamates/chemistry , Phenylcarbamates/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A novel fused tricyclic analog (11) of cytisine has been prepared (coined 'cyfusine') and determined to have high affinity at neuronal nicotinic acetylcholine receptors. A [3+2] cycloaddition protocol permitted entry into a 3,4-differentially difunctionalized dihydropyrrole (7). The penultimate cyclization was accomplished using the modified Van Tamelen conditions developed in our earlier synthesis of (+/-)-cytisine. Sequential ring-forming reactions ([3+2] cycloaddition/cyclopropanation/pyridone cyclization) gives a unique cyclopropyl analog (16) possessing a skeleton isoatomic with that of cytisine.
Subject(s)
Alkaloids/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , Pyridones/chemical synthesis , Pyrroles/chemical synthesis , Receptors, Nicotinic/chemistry , Azocines/chemistry , Cyclization , Cyclopropanes/chemistry , Models, Chemical , Pyridones/chemistry , Pyridones/metabolism , Pyrroles/chemistry , Pyrroles/metabolism , Quinolizines/chemistry , Receptors, Nicotinic/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE10A inhibitory potency and selectivity versus PDE3A/B. These efforts culminated in the discovery of 29, a potent and selective brain penetrable inhibitor of PDE10A.
Subject(s)
Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases/metabolism , Pyrrolidines/chemical synthesis , Quinazolines/chemical synthesis , Animals , Corpus Striatum/metabolism , Crystallography, X-Ray , Cyclic GMP/metabolism , Mice , Models, Molecular , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/chemistry , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Structure-Activity RelationshipABSTRACT
Phosphodiesterase 10A (PDE10A) is a recently identified cyclic nucleotide phosphodiesterase expressed primarily in dopaminoreceptive medium spiny neurons of the striatum. We report that papaverine is a potent, specific inhibitor of PDE10A and use this compound to explore the role of PDE10A in regulating striatal function. Papaverine administration produces an increase in striatal tissue levels of cGMP and an increase in extracellular cAMP measured by microdialysis. These cyclic nucleotide changes are accompanied by increases in the phosphorylation of CREB and ERK, downstream markers of neuronal activation. In rats, papaverine potentiates haloperidol-induced catalepsy, consistent with the hypothesis that inhibition of PDE10A can increase striatal output and prompting a further evaluation of papaverine in models predictive of antipsychotic activity. Papaverine is found to inhibit conditioned avoidance responding in rats and mice and to inhibit PCP- and amphetamine-stimulated locomotor activity in rats. The effects of papaverine on striatal cGMP and CREB and ERK phosphorylation, as well as on conditioned avoidance responding, were absent in PDE10A knockout mice, indicating that the effects of the compound are the result of PDE10A inhibition. These results indicate that PDE10A regulates the activation of striatal medium spiny neurons through effects on cAMP- and cGMP-dependent signaling cascades. Furthermore, the present results demonstrate that papaverine has efficacy in behavioral models predictive of antipsychotic activity. Thus, inhibition of PDE10A may represent a novel approach to the treatment of psychosis.
Subject(s)
Antipsychotic Agents/pharmacology , Corpus Striatum/enzymology , Papaverine/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/physiology , Animals , Avoidance Learning/drug effects , Catalepsy/chemically induced , Central Nervous System Stimulants/pharmacology , Corpus Striatum/metabolism , Cyclic AMP/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic GMP/metabolism , Dendritic Spines/drug effects , Dendritic Spines/physiology , Dextroamphetamine/pharmacology , Drug Synergism , Excitatory Amino Acid Antagonists/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Haloperidol/pharmacology , Mice , Mice, Knockout , Motor Activity/drug effects , Phencyclidine/pharmacology , Phosphorylation , RatsABSTRACT
3,5-Bicyclic aryl piperidines are a new class of high-affinity alpha4beta2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the alpha4beta2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Receptors, Nicotinic/metabolism , Smoking Cessation/methods , Animals , Cyclization , Molecular Structure , Piperidines/classification , Rats , Structure-Activity RelationshipABSTRACT
The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.
Subject(s)
Alkaloids/pharmacology , Carbon/chemistry , Dopamine/metabolism , Nicotinic Agonists/pharmacology , Nucleus Accumbens/drug effects , Receptors, Nicotinic/chemistry , Alkaloids/chemistry , Animals , Azocines/chemistry , Azocines/pharmacology , Nicotinic Agonists/chemistry , Quinolizines/chemistry , Quinolizines/pharmacology , Rats , Receptors, Nicotinic/metabolism , Smoking Cessation , Structure-Activity RelationshipABSTRACT
Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
