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1.  Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 2′-Fluoro-3′-(substituted pyridinyl)-7-deschloroepibatidine Analogues 
Journal of Medicinal Chemistry  2014;57(3):836-848.
2′-Fluoro-3-(substituted pyridine)epibatidine analogues 7a–e and 8a–e were synthesized, and their in vitro and in vivo nAChR properties were determined. 2′-Fluoro-3′-(4″-pyridinyl)deschloroepibatidine (7a) and 2′-fluoro-3′-(3″-pyridinyl)deschloroepibatidine (8a) were synthesized as bioisosteres of the 4′-nitrophenyl lead compounds 5a and 5g. Comparison of the in vitro nAChR properties of 7a and 8a to those of 5a and 5g showed that 7a and 8a had in vitro nAChR properties similar to those of 5a and 5g but both were more selective for the α4β2-nAChR relative to the α3β4- and α7-nAChRs than 5a and 5g. The in vivo nAChR properties in mice of 7a were similar to those of 5a. In contrast, 8a was an agonist in all four mouse acute tests, whereas 5g was active only in a spontaneous activity test. In addition, 5g was a nicotine antagonist in both the tail-flick and hot-plate tests, whereas 8a was an antagonist only in the tail-flick test.
doi:10.1021/jm401602p
PMCID: PMC3983394  PMID: 24428686
2.  4β-Methyl-5-(3-hydroxyphenyl)morphan Opioid Agonist and Partial Agonist Derived from a 4β-Methyl-5-(3-hydroxyphenyl)morphan Pure Antagonist 
Journal of medicinal chemistry  2013;56(21):8826-8833.
In previous studies we reported that addition of 7α-acylamino groups to N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7α-amino (5a), 7α-alkylamino (5b–e), or 7α-dialkylamino (5f–h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-methylamino analogues were full agonists at the μ and δ receptors and antagonists at the κ receptor. The 7α-cyclopropylmethylamino analogue 5h was a full agonist at the μ receptor with weaker agonist activity at the δ and κ receptors. Whereas the addition of a 7α-acylamino group to the pure non-selective opioid receptor antagonist N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to κ selective pure opioid receptor antagonist, the addition of a 7α-amino, 7α-alkylamino or 7α-dialkylamino group to 4 leads to opioid ligands that are largely μ or δ agonist with mixed agonist/antagonist properties.
doi:10.1021/jm401250s
PMCID: PMC3893112  PMID: 24144404
3.  The Effect of the 3- and 4-Methyl Groups on the Opioid Receptor Properties of N-Substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines 
Journal of medicinal chemistry  2014;57(7):3140-3147.
N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2a–b) are opioid receptor antagonists where the antagonist properties are not due to the type of N-substituent. In order to gain a better understanding of the contribution that the 3- and 4-methyl groups make to the pure antagonist properties of 2a–b, we synthesized analogues of 2a–b which lacked the 4-methyl (5a–b), 3-methyl (6a–b) and both the 3- and 4-methyl group (7a–b) and compared their opioid receptor properties. We found that (1) all N-methyl and N-phenylpropyl substituted compounds were non-selective opioid antagonists (2) all N-phenylpropyl analogues were more potent than their N-methyl counterparts and (3) compounds 2a–b which have both a 3- and 4-methyl substituent, were more potent antagonists than analogs 5a–b, 6a–b and 7a–b. We also found that the removal of 3-methyl substituent of N-methyl and N-phenylpropyl 3-methyl-4-(3-hydroxyphenyl)piperazines (8a–b) gives (4a–b) which are opioid antagonists.
doi:10.1021/jm500184j
PMCID: PMC4070716  PMID: 24635568
4.  Discovery of N-{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists 
Journal of medicinal chemistry  2013;56(11):4551-4567.
There is continuing interest in the discovery and development of new κ opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class of opioid receptor antagonists. In this study we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [35S]GTPγS binding assay showed that neither compound showed the high potency and κ opioid receptor selectivity of JDTic. A library of compounds using the core scaffold 21 was synthesized and tested for their ability to inhibit [35S]GTPγS binding stimulated by the selective κ opioid agonist U69,593. These studies led to N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl]-4-phenoxybenzamide (11a), a compound that showed good κ opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [35S]GTPγS binding assay showed that several of the analogues were potent and selective κ opioid receptor antagonists.
doi:10.1021/jm400275h
PMCID: PMC3701944  PMID: 23651437
5.  Development of Kappa Opioid Receptor Antagonists 
Journal of medicinal chemistry  2013;56(6):2178-2195.
Kappa opioid receptors (KORs) belong to the G-protein coupled class of receptors (GPCRs). They are activated by the endogenous opioid peptide dynorphin (DYN) and expressed at particularly high levels within brain areas implicated in modulation of motivation, emotion, and cognitive function. Chronic activation of KORs in animal models has maladaptive effects including increases in behaviors that reflect depression, the propensity to engage in drug-seeking behavior, and drug craving. The fact that KOR activation has such a profound influence on behaviors often triggered by stress has led to interest in selective KOR antagonists as potential therapeutic agents. This perspective provides a description of preclinical research conducted in the development of several different classes of selective KOR antagonists, a summary of the clinical studies conducted thus far, and recommendations for the type of work needed in the future to determine if these agents would be useful as pharmacotherapies for neuropsychiatric illness.
doi:10.1021/jm301783x
PMCID: PMC3612131  PMID: 23360448
6.  Synthesis and Nicotinic Acetylcholine Receptor In Vitro and In Vivo Pharmacological Properties of 2'-Fluoro-3'-(substituted phenyl)deschloroepibatidine Analogues of 2'-Fluoro-3'-(4-nitrophenyl)deschloroepibatidine (4-Nitro-PFEB or RTI-7527-102) 
Journal of medicinal chemistry  2012;55(14):6512-6522.
Herein, we report the synthesis and nicotinic acetylcholine receptor (nAChR) in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidines 5b–g, analogues of 3'-(4-nitrophenyl) compound 5a. All compounds had high affinity for the α4β2-nAChR and low affinity for α7-nAChR. Initial electrophysiological studies showed that all analogues were antagonists at α4β2-, α3β4-, and α7-nAChRs. The 4-carbamoylphenyl analogue 5g was highly selective for α4β2-nAChR over α3β4- and α7-nAChRs. All the analogues were antagonists of nicotine-induced antinociception in the tail-flick test. Molecular modeling docking studies using agonist-bound form of the X-ray crystal structure of the acetylcholine binding protein suggested several different binding modes for epibatidine, varenicline, and 5a–5g. In particular, a unique binding mode for 5g was suggested by these docking simulations. The high binding affinity, in vitro efficacy, and selectivity of 5g for α4β2-nAChR combined with its nAChR functional antagonist properties suggest that 5g will be a valuable pharmacological tool for studying the nAChR and may have potential as a pharmacotherapy for addiction and other CNS disorders.
doi:10.1021/jm300575y
PMCID: PMC3431023  PMID: 22742586
Nicotinic receptors; epibatidine; nicotinic antagonist; α4β2-nAChR selectivity; electrophysiological studies; tail-flick; hot-plate; molecular modeling
7.  Nicotinic Acetylcholine Receptor Efficacy and Pharmacological Properties of 3-(Substituted phenyl)-2β-substituted Tropanes 
Journal of medicinal chemistry  2010;53(23):8345-8353.
There is a need for different and better aids to tobacco product use cessation. Useful smoking cessation aids, bupropion (2) and varenicline (3), share some chemical features with 3-phenyltropanes (4), which have promise in cocaine dependence therapy. Here we report studies to generate and characterize pharmacodynamic features of 3-phenyltropane analogues. These studies extend our work on the multiple molecular target model for aids to smoking cessation. We identified several new 3-phenyltropane analogues that are superior to 2 in inhibition of dopamine, norepinephrine, and sometimes serotonin reuptake. All of these ligands also act as inhibitors of nicotinic acetylcholine receptor (nAChR) function with a selectivity profile that favors, like 2, inhibition of α3β4*-nAChR. Many of these ligands also block acute effects of nicotine-induced antinociception, locomotor activity, and hypothermia. Importantly, all except one of the analogues tested have better potencies in inhibition of nicotine conditioned place preference than 2. We have identified new compounds that have utility as research tools and possible promise for treatment of nicotine dependence.
doi:10.1021/jm100994w
PMCID: PMC3130825  PMID: 21058665
Nicotine; 3-phenyltropanes; structure activity relationship; dopamine uptake norepinephrine uptake; nAChR antagonism; antinociception; locomotor activity; hypothermia multiple target; conditioned place preference
8.  Synthesis of 2-(Substituted phenyl)-3,5,5-trimethylmorpholine Analogues and Their Effects on Monoamine Uptake, Nicotinic Acetylcholine Receptor Function, and Behavioral Effects of Nicotine 
Journal of medicinal chemistry  2011;54(5):1441-1448.
Toward development of smoking cessation aids superior to bupropion (2), we describe synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues 5a–5h and their effects on inhibition of dopamine, norepinephrine, and serotonin uptake, nicotinic acetylcholine receptor (nAChR) function, acute actions of nicotine, and nicotine-conditioned place preference (CPP). Several analogues encompassing aryl substitutions, N-alkylation, and alkyl extensions of the morpholine ring 3-methyl group provided analogues more potent in vitro than (S,S)-hydroxybupropion (4a) as inhibitors of dopamine or norepinephrine uptake and antagonists of nAChR function. All of the new (S,S)-5 analogues had better potency than (S,S)-4a as blockers of acute nicotine analgesia in the tail-flick test. Two analogues with highest potency at α3β4*-nAChR and among the most potent transporter inhibitors have better potency than (S,S)-4a in blocking nicotine-CPP. Collectively, these findings illuminate mechanisms of action of 2 analogues and identify deshydroxybupropion analogues 5a–5h as possibly superior candidates as aids to smoking cessation.
doi:10.1021/jm1014555
PMCID: PMC3048909  PMID: 21319801
Nicotine; bupropion; hydroxybupropion; structure activity relationship; dopamine uptake; norepinephrine uptake; nAChR antagonism; antinociception; locomotor activity; hypothermia
9.  Analogues of (3R)-7-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic). Synthesis and In Vitro and In Vivo Opioid Receptor Antagonist Activity 
Journal of medicinal chemistry  2010;53(14):5290-5301.
The synthesis of compounds 6, 7a,b, 8a,b, 9a,b, and 10a,b where the amino -NH- group of JDTic (3) was replaced with an aromatic =CH–, CH2, O, S, or SO group was accomplished and used to further characterize the SAR of the compound 3 class of κ opioid receptor antagonists. All of the compounds showed subnanomolar to low nanomolar Ke values at the κ opioid receptor. The most potent compound was 7a, where the amino -NH- group of 3 was replaced by a methylene (-CH2-) group. This compound had a Ke = 0.18 nM and was 37- and 248-fold selective for the κ relative to the μ and δ opioid receptors, respectively. Similar to compound 3, compound 7a antagonized selective κ agonist U50,488-induced diuresis after s.c. administration in rats. In contrast to 3, where κ antagonist activity lasted for three weeks, compound 7a did not show any κ antagonist activity after one week.
doi:10.1021/jm1004978
PMCID: PMC2912403  PMID: 20568781
10.  Synthesis and Characterization of In Vitro and In Vivo Profiles of Hydroxybupropion Analogues: Aids to Smoking Cessation 
Journal of medicinal chemistry  2010;53(12):4731-4748.
To create potentially superior aids to smoking cessation and/or antidepressants and to elucidate bupropion’s possible mechanisms of action(s), several analogues based on its active hydroxymetabolite (2S,3S)-4a were synthesized and tested for their abilities to inhibit monoamine uptake and nAChR subtype activities in vitro and acute effects of nicotine in vivo. The 3′,4′-dichlorophenyl [(±)-4n], naphthyl (4r), and 3-chlorophenyl or 3-propyl analogues 4s and 4t, respectively, had higher inhibitory potency and/or absolute selectivity than (2S,3S)-4a for inhibition of DA, NE, or 5HT uptake. The 3′-fluorophenyl, 3′-bromophenyl, and 4-biphenyl analogues 4c, 4d, and 4l, respectively, had higher potency for antagonism of α4β2-nAChR than (2S,3S)-4a. Several analogues also had higher potency than (2S,3S)-4a as antagonists of nicotine-mediated antinociception in the tail-flick assay. The results suggest that compounds acting via some combination of DA, NE, or 5HT inhibition and/or antagonism of α4β2-nAChR can potentially be new pharmacotherapeutics for treatment of nicotine dependence.
doi:10.1021/jm1003232
PMCID: PMC2895766  PMID: 20509659
Nicotine; bupropion; hydroxybupropion; structure activity relationship; dopamine uptake; norepinephrine uptake; nAChR antagonism; antinociception; locomotor activity; hypothermia
11.  Synthesis and Biological Evaluation of Bupropion Analogues as Potential Pharmacotherapies for Smoking Cessation 
Journal of medicinal chemistry  2010;53(5):2204-2214.
Bupropion (2a) analogues were synthesized and tested for their ability to inhibit monoamine uptake and to antagonize the effects of human α3β4*, α4β2, α4β4, and α1* nAChRs. The analogues were evaluated for their ability to block nicotine-induced effects in four tests in mice. Nine analogues showed increased monoamine uptake inhibition. Similar to 2a all but one analogue show inhibition of nAChR function selective for human α3β4*-nAChR. Nine analogues have higher affinity at α3β4*-nAChRs than 2a. Four analogues also had higher affinity for α4β2 nAChR. Analogues 2r, 2m, and 2n with AD50 values of 0.014, 0.015, and 0.028 mg/kg were 87, 81, and 43 times more potent than 2a in blocking nicotine-induced antinociception in the tail-flick test. Analogue 2x with IC50 values of 31 and 180 nM for DA and NE, respectively, and IC50 = 0.62 and 9.8 μm for antagonism of α3β4 and α4β2 nAChRs had the best overall in vitro profile relative to 2a.
doi:10.1021/jm9017465
PMCID: PMC2841507  PMID: 20158204
Nicotine; bupropion; structure activity relationship; dopamine uptake; norepinephrine uptake; nAChR antagonism; antinociception; locomotor activity; hypothermia; multiple target
12.  The Synthesis of Haptens and Their Use for the Development of Monoclonal Antibodies for Treating Methamphetamine Abuse 
Journal of medicinal chemistry  2009;52(22):7301-7309.
In addition to addiction, the repeated use of (+)-methamphetamine [(+)-METH], (+)amphetamine [(+)-AMP], or (±)-methylenedioxymethamphetamine [(±)-MDMA, commonly called ecstasy] can lead to life-threatening medical problems including cardiovascular injury, severe depression, and psychosis. Currently, there are no specific pharmacotherapies to treat these medical problems. In this study, we report the design and synthesis of two haptens, (S)-(+)-3-(9-carboxynonyloxy)methamphetamine [3a, (+)-METHMO10] and (S)-(+)-3-(5-carboxypentyloxy)methamphetamine [3b, (+)-METH MO6], and their use in generating high affinity (low KD value) monoclonal antibodies (mAbs) against (+)-METH, (+)-AMP, and/or (+)-MDMA. Based on results from the determination of mAb KD values and ligand specificity, the mAbs generated from hapten 3a showed the greatest promise for generating active and passive immunotherapies for treating overdose or addiction from (+)-METH-like stimulants.
doi:10.1021/jm901134w
PMCID: PMC2787402  PMID: 19877685
13.  Development of 3-Phenyltropane Analogs with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter 
Journal of medicinal chemistry  2008;51(24):8048-8056.
Previous studies showed that the mixed monoamine transporter inhibitor (6, RTI-112) reduced cocaine self-administration at a high level of serotonin transporter (5-HTT) occupancy with no detectable dopamine transporter (DAT) occupancy. In this study, a series of 3β-(substituted phenyl)tropane-2β-carboxylic acid methyl esters 7a-g, 3β-(4-methoxyphenyl)tropane-2β-carboxylic acid esters 8a-j, and 3β-(4-methoxyphenyl)-2β-[3-(4′-methylphenyl)isoxazol-5-yl]tropane (9) were synthesized and evaluated for their monoamine transporter binding affinities to identify potent and selective compounds for both the DAT and 5-HTT relative to the norepinephrine transporter (NET). A number of compounds showed high binding affinities for both the DAT and 5-HTT and low affinity for the NET. 3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) with an IC50 value of 2.5 nM for the DAT and Ki values of 3.5 nM and 2040 nM for the 5-HTT and NET, respectively, is the most potent and selective compound for the DAT and 5-HTT relative to the NET in this study.
doi:10.1021/jm801162z
PMCID: PMC2841478  PMID: 19053748
14.  N-Substituted cis-4a-(3-Hydroxyphenyl)-8a-methyloctahydroisoquinolines Are Opioid Receptor Pure Antagonists 
Journal of medicinal chemistry  2005;48(26):8182-8193.
N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a–g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a–g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has the lower potential energy relative to the axial conformation. Evaluation of compounds 6a–g in the [35S]GTP-γ-S in vitro functional assay showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a Ke of 0.27 nM at the κ opioid receptor with 154- and 46-fold selectively relative to the μ and δ receptors, respectively, possessed the best combination of κ potency and selectivity.
doi:10.1021/jm058261c
PMCID: PMC2585695  PMID: 16366600

Results 1-14 (14)