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1.  Recent Developments in Novel Antidepressants Targeting α4β2-Nicotinic Acetylcholine Receptors 
Journal of Medicinal Chemistry  2014;57(20):8204-8223.
Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.
PMCID: PMC4207546  PMID: 24901260
2.  Identification of Novel α4β2-Nicotinic Acetylcholine Receptor (nAChR) Agonists Based on an Isoxazole Ether Scaffold that Demonstrate Antidepressant-like Activity 
Journal of Medicinal Chemistry  2012;55(2):812-823.
There is considerable evidence to support the hypothesis that the blockade of nAChR is responsible for the antidepressant action of nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, has been shown to be an effective add-on in patients that do not respond to selective serotonin reuptake inhibitors. This suggests that nAChR ligands may address an unmet clinical need by providing relief from depressive symptoms in refractory patients. In this study, a new series of nAChR ligands based on an isoxazole-ether scaffold have been designed and synthesized for binding and functional assays. Preliminary structure-activity relationship (SAR) efforts identified a lead compound 43, which possesses potent antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical mouse forced swim test. Early stage absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) studies also suggested favorable drug-like properties, and broad screening towards other common neurotransmitter receptors indicated that compound 43 is highly selective for nAChRs over the other 45 neurotransmitter receptors and transporters tested.
PMCID: PMC3272775  PMID: 22148173
3.  Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile 
Journal of Medicinal Chemistry  2012;55(2):717-724.
Despite their discovery in the early 20th century and intensive study over the last twenty years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing α4β2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity, while acting as partial agonists at α4β2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening towards other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other α4β2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.
PMCID: PMC3292870  PMID: 22171543
4.  Discovery of Isoxazole Analogs of Sazetidine-A as Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists for the Treatment of Depression 
Journal of medicinal chemistry  2011;54(20):7280-7288.
Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenalin are not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogs that interact with α4β2-nAChR as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary ADMET studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450 related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.
PMCID: PMC3197876  PMID: 21905669
5.  Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice 
ChemMedChem  2011;6(9):1593-1602.
Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5 million people in the United States. Current treatment regimes include the so-called “mood-stabilizing drugs”, such as lithium and valproate that are relatively dated drugs with various known side effects. Glycogen synthase kinase-3β (GSK-3β) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3β. We designed a series of second generation benzofuran-3-yl-(indol-3-yl)maleimides containing a piperidine ring that possess IC50 values in the range of 4 to 680 nm against human GSK-3β. One of these compounds exhibits reasonable kinase selectivity and promising preliminary absorption, distribution, metabolism, and excretion (ADME) data. The administration of this compound at doses of 10 to 25 mgkg−1 resulted in the attenuation of hyperactivity in amphetamine/ chlordiazepoxide-induced manic-like mice together with enhancement of prepulse inhibition, similar to the effects found for valproate (400 mgkg−1) and the antipsychotic haloperidol (1 mgkg−1). We also tested this compound in mice carrying a mutation in the central transcriptional activator of molecular rhythms, the CLOCK gene, and found that the same compound attenuates locomotor hyperactivity in response to novelty. This study further demonstrates the use of inhibitors of GSK-3β in the treatment of manic episodes of bipolar/mood disorders, thus further validating GSK-3β as a relevant therapeutic target in the identification of new therapies for bipolar patients.
PMCID: PMC3428230  PMID: 21732538
antimanic agents; bipolar disorder; circadian rhythms; CLOCK mutant mice; GSK-3 inhibitors
6.  RGS9-2: probing an intracellular modulator of behavior as a drug target 
Regulators of G-protein signaling (RGS proteins) comprise a large family of signal transduction molecules that modulate G-protein-coupled-receptor (GPCR) function. Among the RGS proteins expressed in the brain, RGS9-2 is very abundant in the striatum, a brain region involved in movement, motivation, mood and addiction. This protein negatively modulates signal transduction thus playing a key part in striatal function and resultant behavioral responses. In particular, there is evidence of important interactions with μ-opioid- and dopamine D2-receptor signaling pathways. Several studies indicate that manipulations of RGS9-2 levels in the striatum might greatly affect pharmacological responses. These findings indicate that treatment strategies targeting RGS9-2 levels or activity might be used to enhance responses to drugs acting at GPCRs and/or prevent undesired drug actions.
PMCID: PMC3394094  PMID: 19211160
7.  Dissociation between duration of action in the forced swim test and nicotinic acetylcholine receptor occupancy with sazetidine, varenicline, and 5-I-A85380 
Psychopharmacology  2011;217(2):199-210.
Nicotinic acetylcholine receptor (nAChR) agonists, partial agonists and antagonists have antidepressant-like effects in rodent models and reduce symptoms of depression in humans.
The aim of this study was to determine if the β2* partial agonist sazetidine-A (sazetidine) showed an antidepressant-like effect in the forced swim test that was mediated by β2* nAChRs activation or desensitization.
Sazetidine, the less selective β2* partial agonist varenicline and the full β2* agonist 5-I-A8350, exhibited acute antidepressant-like effects in the forced swim test. The role of β2* nAChRs was confirmed by results showing 1) reversal of sazetidine’s antidepressant-like effects in the forced swim test by nAChR antagonists mecamylamine and dihydro-β-erythroidine (DHβE); 2) no effect of sazetidine in mice lacking the β2 subunit of the nAChR; and 3) a high correspondence between behaviorally active doses of sazetidine and β2* receptor occupancy. β2* receptor occupancy following acute sazetidine, varenicline, and 5-I-A8350 extended beyond the duration of action in the forced swim test. The long lasting receptor occupancy of sazetidine did not diminish behavioral efficacy in the forced swim test following repeated dosing.
These results demonstrate that activation of β2* nAChRs mediate sazetidine’s antidepressant-like actions and suggest that ligands that activate β2* nAChRs would be promising targets for the development of a new class of antidepressant.
PMCID: PMC3266849  PMID: 21487659
nicotinic receptor; antidepressant; sazetidine-A; AMOP-H-OH; varenicline; 5-I-A85380; receptor occupancy; forced swim
8.  Chemistry and Pharmacological Characterization of Novel Nitrogen Analogs of AMOP-H-OH (Sazetidine-A; 6-[5-(Azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) as α4β2-Nicotinic Acetylcholine Receptor-Selective Partial Agonists 
Journal of medicinal chemistry  2010;53(19):6973-6985.
In order to advance therapeutic applications of nicotinic ligands, continuing research efforts are being directed toward the identification and characterization of novel nicotinic acetylcholine receptor (nAChR) ligands that are both potent and subtype selective. Herein we report the synthesis and pharmacological evaluation of members of a new series of 3-alkoxy-5-aminopyridine derivatives that display good selectivity for the α4β2-nAChR subtype based on ligand binding and functional evaluations. The most potent ligand in this series, compound 64, showed high radioligand binding affinity and selectivity for rat α4β2-nAChR with a Ki value of 1.2 nM and 4700-fold selectivity for α4β2-over α3β4-nAChR, and ~100-fold selectivity for functional, high-sensitivity, human α4β2-nAChR over α3β4*-nAChR. In the mouse forced swim test, compound 64 exhibited antidepressant-like effects. Structure-activity relationship (SAR) analyses suggest that the introduction of additional substituents to the amino group present on the pyridine ring of the N-demethylated analogue of compound 17 can provide potent α4β2-nAChR-selective ligands for possible use in treatment of neurological and psychiatric disorders including depression.
PMCID: PMC2957884  PMID: 20822184
9.  Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents 
The present studies assessed the potential abuse liability and likely mechanism(s) of action of the wake-promoting agent modafinil.
Experiments assessed the locomotor sensitization (LS) and discriminative stimulus (DS) properties of modafinil in mouse and rat, respectively. Comparative data were generated with a range of psychostimulants and monoamine reuptake inhibitors.
Repeated administration of d-amphetamine and cocaine, psychostimulants with high abuse liability, resulted in the induction and expression of LS in mice. Bupropion and caffeine, two psychostimulants not abused in humans, were not associated with LS. GBR12909 induced LS during repeated exposure, but there was no evidence of expression of LS after acute challenge following withdrawal. In contrast, repeated administration of modafinil resulted in the expression, but not induction, of LS. d-amphetamine, but not the μ-opioid agonist morphine or the nAChR agonist nicotine, fully substituted for the cocaine DS in rats. The selective dopamine transporter (DAT) inhibitor GBR12909 fully substituted, the preferential norepinephrine transporter (NET) inhibitor desipramine partially substituted, and the selective serotonin reuptake inhibitor citalopram failed to substitute for cocaine. Modafinil fully substituted for cocaine, similar to the mixed DAT/NET inhibitor bupropion.
Two preclinical assays indicated potential abuse liability of modafinil; drug discrimination studies suggest DAT blockade by modafinil is a likely mechanism of action in vivo.
PMCID: PMC2880855  PMID: 20346966
modafinil; locomotor sensitization; drug discrimination; cocaine; d-amphetamine; bupropion; citalopram; desipramine; GBR12909; caffeine; morphine; nicotine; rat; mouse
10.  Chemistry and Pharmacology of Nicotinic Ligands Based on 6-[5-(Azetidin-2-ylmethoxy) pyridin-3-yl]hex-5-yn-1-ol (AMOP-H-OH) for Possible Use in Depression 
ChemMedChem  2009;4(8):1279-1291.
AMOP-H-OH (6-[5-(azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) and some of its sulfur-bearing analogs were tested for their actions in vitro at human α4β2-, α4β4-, α3β4*- and α1*-nicotinic acetylcholine receptors (nAChRs). AMOP-H-OH also was assessed in a model of antidepressant efficacy. AMOP-H-OH and some of its analogs have high potency and selectivity for α4β2-nAChRs over other nAChR subtypes. Effects are manifest as partial agonism, perhaps reflecting selectivity for high sensitivity (α4)3(β2)2-nAChRs. More prolonged exposure to AMOP-H-OH and its analogs produces inhibition of subsequent responses to acute challenges with nicotinic full agonists, again selectively for α4β2-nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of α4β2-nAChRs is limited by the drugs’ activities as partial agonists. Certain aspects of the in vitro pharmacology suggest that AMOP-H-OH and some of its analogs have a set of binding sites on α4β2-nAChRs that are distinct from those for full agonists. The in vitro pharmacological profile suggests that peripheral side effects of AMOP-H-OH or its analogs would be minimal and that their behavioral effects would be dominated by central nAChR actions. AMOP-H-OH also has profound and high potency antidepressant-like effects in the forced swim test. The net action of prolonged exposure to AMOP-H-OH or its analogs, as for nicotine, seems to be a selective decrease in α4β2-nAChR function. Inactivation of nAChRs may be a common neurochemical endpoint for nicotine dependence, its treatment, and some of its manifestations, including relief from depression.
PMCID: PMC2955514  PMID: 19569163
nicotine; nAChRs; depression; α4β2; Sazetidine-A; AMOP-H-OH
11.  Selective 5-Hydroxytrytamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine – Identification of Drugs with Antidepressant-Like Action 
Journal of medicinal chemistry  2009;52(7):1885-1902.
We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT2C agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT2C receptor agonists with selectivity over both 5-HT2A and 5-HT2B receptors in functional assays. The most promising compound is 37 with 120- and 14-fold selectivity over 5-HT2A and 5-HT2B, respectively (EC50 = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10–60 mg/kg) decreased immobility time in the mouse forced swim test.
PMCID: PMC2832311  PMID: 19284718
12.  Sex differences in anxiety-like behavior and locomotor activity following chronic nicotine exposure in mice 
Neuroscience letters  2008;439(2):187-191.
Smoking appears to increase overall levels of stress, despite self-reports that men and women smoke to control symptoms of anxiety. The overall incidence of anxiety disorders is also significantly higher in women. This study examined whether behavioral sensitivity to chronic nicotine varies across sexes in mice. Male and female C57BL/6J mice were exposed chronically to nicotine in the drinking water (50, 100, or 200 µg/ml) and tested for locomotor activation and anxiety-like behavior in the elevated plus maze (EPM). Female mice were less sensitive to locomotor activation. Whereas both males and females showed increases in locomotor activity at the highest (200 µg/ml) concentration of nicotine, only males showed locomotor activation at the middle (100 µg/ml) concentration. The decreased sensitivity in females could not be explained by reduced nicotine intake compared to males. In the EPM, nicotine produced an anxiogenic-like response in females, but had no effect in males. Treatment with the high (200 µg/ml) dose of nicotine reduced the amount of time spent in the open arms of the EPM in female, but not male mice. No differences in the anxiogenic-like response to chronic nicotine was observed between β2-subunit knockout and wildtype mice, suggesting that β2-subunit containing nicotinic receptors do not mediate the anxiogenic-like response to chronic nicotine in females. This shows that female mice have an anxiogenic-like response to chronic nicotine, but are less sensitive to nicotine’s psychostimulant properties, which may be related to the increased relapse to smoking following abstinence in women.
PMCID: PMC2491450  PMID: 18524488
C57BL/6J mice; nicotine; elevated plus maze; locomotor activity; nicotinic acetylcholine receptor; knockout mice

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