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1.
Neuropharmacology ; 123: 233-241, 2017 Sep 01.
Article in English | MEDLINE | ID: mdl-28623171

ABSTRACT

Although the muscarinic receptor family has long been a source of potentially compelling targets for small molecule drug discovery, it was difficult to achieve agonist selectivity within the family. A new class of M1 muscarinic agonists has emerged, and these compounds have been characterized as agonists that activate the receptor at an allosteric site. Members of this class of M1 agonists have been shown to be selective across the muscarinic receptors. However, upon introduction of a novel pharmacologic mechanism, it is prudent to ensure that no new off-target activities have arisen, particularly within the context of in vivo experiments. Reported here, is the in vitro and in vivo characterization of a novel M1 agonist tool compound, PPBI, and demonstrations that the primary biological effects of PPBI are mediated through M1. PPBI reverses d-amphetamine locomotor activity, but fails to do so in transgenic mice that do not express M1. PPBI also reverses a natural deficit in a rat cognition model at a level of exposure which also activates cortical circuitry. Most notably, PPBI is analgesic in a variety of rat and mouse models and the analgesic effect of PPBI is reversed by an M1-preferring antagonist and an M1-selective toxin. Finally, the pharmacokinetic/pharmacodynamic measures of PPBI are compared across multiple endpoints which highlights that activity in models of psychosis and pain require higher exposures than that required in the cognition model.


Subject(s)
Analgesics/pharmacology , Benzimidazoles/pharmacology , Muscarinic Agonists/pharmacology , Nootropic Agents/pharmacology , Piperidines/pharmacology , Pyrrolidines/pharmacology , Receptor, Muscarinic M1/agonists , Amphetamine/pharmacology , Analgesics/chemistry , Analgesics/pharmacokinetics , Animals , Brain/drug effects , Brain/metabolism , CHO Cells , Central Nervous System Stimulants/pharmacology , Cognition/drug effects , Cricetulus , Disease Models, Animal , Humans , Male , Mice, Inbred C57BL , Mice, Knockout , Molecular Structure , Motor Activity/drug effects , Muscarinic Agonists/chemistry , Muscarinic Agonists/pharmacokinetics , Nootropic Agents/chemistry , Nootropic Agents/pharmacokinetics , Pain/drug therapy , Random Allocation , Rats, Sprague-Dawley , Receptor, Muscarinic M1/genetics , Receptor, Muscarinic M1/metabolism , Transfection
2.
Neuropharmacology ; 77: 475-80, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24490229

ABSTRACT

Many neuropsychiatric drugs interact with more than one molecular target, and therapeutic indices might be improved by prospectively designing compounds with profiles optimized against a combination of targets. The dibenzo-epine scaffold is considered a privileged structure, and this scaffold has been explored rigorously in the search for potential novel neuropharmacologic treatments. Members of this chemical class are known to interact with many receptors and transporters, particularly those of the biogenic amine class. In this study, four points of diversity within a dibenzo-epine scaffold were varied systematically and the pharmacologic profiles of the compounds were assessed across 14 receptors and transporters thought to be important to clinical profiles of efficacy and safety. The resulting data were analyzed using a modified forward selection linear regression procedure, thus revealing potential pharmacophoric relationships of the assessed targets within this chemical class. The results highlight a strong covariance across numerous targets. Moreover, the outcome quantifies the innately problematic issue of prospectively designing compounds with defined affinities across multiple targets. Finally, an exploration of the correspondence of binding affinities to in vitro functional activity reveals an additional layer of complexity central to prospectively designing compounds to engage multiple targets. The apparent relatedness of the 5-HT(2a) and D2 activities suggests that the structural pharmacophores of these receptors overlap more closely with each other than with members of their respective families.


Subject(s)
Antidepressive Agents/pharmacology , Antipsychotic Agents/pharmacology , Radioligand Assay , Receptors, Dopamine/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Serotonin/metabolism , Cell Line , Humans , Ligands
3.
Bioorg Med Chem Lett ; 23(2): 543-7, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23237836

ABSTRACT

Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.


Subject(s)
Benzazepines/chemical synthesis , Benzazepines/pharmacology , Dopamine Agonists/chemical synthesis , Dopamine Agonists/pharmacology , Receptors, Dopamine D2/agonists , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Benzazepines/chemistry , Biological Assay , Disease Models, Animal , Dopamine Agonists/chemistry , Drug Partial Agonism , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Binding/drug effects , Rats , Structure-Activity Relationship
4.
J Pharmacol Exp Ther ; 339(2): 567-78, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21825000

ABSTRACT

The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients.


Subject(s)
Benzopyrans/pharmacology , Benzopyrans/pharmacokinetics , Morpholines/pharmacology , Morpholines/pharmacokinetics , Protein Binding/drug effects , Receptor, Serotonin, 5-HT1B/metabolism , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Serotonin 5-HT1 Receptor Antagonists/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B/analysis , Animals , Anti-Anxiety Agents/blood , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/pharmacology , Behavior, Animal/drug effects , Benzopyrans/blood , Benzopyrans/chemistry , Disease Models, Animal , Dogs , Double-Blind Method , Guinea Pigs , Hepatocytes/drug effects , Humans , Hypothermia, Induced , Macaca fascicularis , Male , Microsomes, Liver/drug effects , Molecular Targeted Therapy , Morpholines/blood , Morpholines/chemistry , Radioligand Assay , Rats, Sprague-Dawley , Serotonin 5-HT1 Receptor Antagonists/blood , Serotonin 5-HT1 Receptor Antagonists/chemistry , Serotonin Receptor Agonists/adverse effects , Serotonin Receptor Agonists/pharmacology , Translational Research, Biomedical
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