Hernán A Navarro

Research Triangle Park Laboratories, Inc., Raleigh, North Carolina, United States

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Publications (113)382.78 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: 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.
    Journal of Medicinal Chemistry 03/2014; · 5.61 Impact Factor
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    ABSTRACT: A set of aporphine analogs related to nantenine was evaluated for antagonist activity at 5-HT2A and α1A adrenergic receptors. With regards to 5-HT2A receptor antagonism, a C2 allyl group is detrimental to activity. The chiral center of nantenine is not important for 5-HT2A antagonist activity, however the N6 nitrogen atom is a critical feature for 5-HT2A antagonism. Compound 12b was the most potent 5-HT2A aporphine antagonist identified in this study and has similar potency to previously identified aporphine antagonists 2 and 3. The ring A and N6 modifications examined were detrimental to α1A antagonism. A slight eutomeric preference for the R enantiomer of nantenine was observed in relation to α1A antagonism.
    Bioorganic & medicinal chemistry letters 03/2014; · 2.65 Impact Factor
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    ABSTRACT: 2'-Fluoro-3-(substituted pyridine)epibatidine analogues 7a-e and 8a-e were synthesized and their in vitro and in vivo nAChR properties 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 as 8a was only an antagonist in the tail-flick test.
    Journal of Medicinal Chemistry 01/2014; · 5.61 Impact Factor
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    ABSTRACT: Bupropion, introduced as an antidepressant in the 1980s, is also effective as a smoking cessation aid and is beneficial in the treatment of methamphetamine addiction, cocaine dependence, addictive behaviors such as pathological gambling, and attention deficit hyperactivity disorder. (2S,3S)-hydroxybupropion is an active metabolite of bupropion produced in humans that contributes to antidepressant and smoking cessation efficacy and perhaps benefits in other CNS disorders. Mechanisms underlying its antidepressant and smoking abstinence remain elusive. However, it seems likely that efficacy is due to a combination of the effects of bupropion and/or its active metabolite (2S,3S)-hydroxybupropion involving the inhibition of reuptake of dopamine (DA) and NE in reward centers of the brain and the noncompetitive antagonism of α4β2- and α3β4*-nAChRs. These combined effects of bupropion and its active metabolite may be responsible for its ability to decrease nicotine reward and withdrawal. Studies directed toward development of a bupropion analog for treatment of cocaine addiction led to compounds, typified by 2-(N-cyclopropylamino)-3'-chloropropiophenone (RTI-6037-39), thought to act as indirect DA agonists. In addition, (2S,3S)-hydroxybupropion analogs were developed, which had varying degrees of DA and NE uptake inhibition and antagonism of nAChRs. These compounds will be valuable tools for animal behavioral studies and as clinical candidates. Here, we review the (1) early studies leading to the development of bupropion, (2) bupropion metabolism and the identification of (2S,3R)-hydroxybupropion as an active metabolite, (3) mechanisms of bupropion and metabolite action, (4) effects in animal behavioral studies, (5) results of clinical studies, and (6) development of bupropion analogs as potential pharmacotherapies for treating nicotine and cocaine addiction.
    Advances in pharmacology (San Diego, Calif.) 01/2014; 69:177-216.
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    ABSTRACT: 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.
    Journal of Medicinal Chemistry 10/2013; · 5.61 Impact Factor
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    ABSTRACT: 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 [(35)S]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 [(35)S]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 [(35)S]GTPγS binding assay showed that several of the analogues were potent and selective κ opioid receptor antagonists.
    Journal of Medicinal Chemistry 05/2013; · 5.61 Impact Factor
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    ABSTRACT: 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 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 the agonist-bound form of the X-ray crystal structure of the acetylcholine binding protein suggested several different binding modes for epibatidine, varenicline, and 5a-g. 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 central nervous system disorders.
    Journal of Medicinal Chemistry 06/2012; 55(14):6512-22. · 5.61 Impact Factor
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    ABSTRACT: In an effort to discover potent and selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonists, 15 tetrahydropyrimidinone analogues of 1-(3-chlorophenyl)-3-(1-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-urea (fenobam) were synthesized. These compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. The IC(50) value for 1-(3-chlorophenyl)-3-(1-methyl-4-oxo-1,4,5,6-tetrahydropyridine)urea (4g) was essentially identical to that of fenobam.
    ACS Medicinal Chemistry Letters 12/2011; 2(12):882-884. · 3.31 Impact Factor
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    ABSTRACT: A series of C1, C2, C3 and N6 analogs of nantenine (2) was synthesized and evaluated in 5-HT(2A) and α(1A) receptor functional assays. Alkyl substitution of the C1 and N6 methyl groups of nantenine provided selective 5-HT(2A) and α(1A) antagonists, respectively. The C2 alkyloxy analogs studied were generally selective for α(1A) versus 5-HT(2A). The C3 bromo analog 15 is one of the most potent aporphinoid 5-HT(2A) antagonists known presently.
    Bioorganic & medicinal chemistry 08/2011; 19(19):5861-8. · 2.82 Impact Factor
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    ABSTRACT: In previous studies we showed that 3-(substituted phenylethynyl)-5-methyl[1,2,4]triazine analogues of MPEP were potent antagonists of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. In the present study we report the synthesis and evaluation of six 3-(substituted biphenylethynyl)-5-methyl[1,2,4]triazines (5a-f), and five 3-(substituted phenoxyphenylethynyl)-5-methyltriazines (6a-e). Compound 2-(4-fluorophenyl-5-[2-(5-methyl[1,2,4]triazine-3-yl)ethynyl]benzonitrile (5f) with an IC(50) of 28.2 nM was the most potent analogue.
    Organic & Biomolecular Chemistry 06/2011; 9(11):4276-86. · 3.57 Impact Factor
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    ABSTRACT: 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.
    Journal of Medicinal Chemistry 02/2011; 54(5):1441-8. · 5.61 Impact Factor
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    ABSTRACT: In this study, we compared the in vitro and in vivo neuronal nicotinic acetylcholine receptor (nAChR) properties of 1,2,3,3a,4,8b-hexahydro-2-benzyl-6-N,N-dimethylamino-1-methylindeno[1,2,-b]pyrrole (HDMP, 4) to that of negative allosteric modulator (NAM), PCP. Patch-clamp experiments showed that HDMP exhibited an inhibitory functional activity at α7 nAChRs with an IC(50) of 0.07 μM, and was 357- and 414-fold less potent at α4β2 and α3β4 nAChRs, with IC(50)s of 25.1 and 29.0 μM, respectively. Control patch-clamp experiments showed that PCP inhibited α7, α4β2 and α3β4 nAChRs with IC(50)s of to 1.3, 29.0 and 6.4 μM, respectively. Further, HDMP did not exhibit any appreciable binding affinity to either α7 or α4β2 nAChRs, suggesting its action via a non-competitive mechanism at these neuronal nAChR subtypes. The in vivo study showed that HDMP was a potent antagonist of nicotine-induced analgesia in the tail-flick (AD(50)=0.008 mg/kg), but not in the hot-plate test. All together, our in vitro and in vivo data suggest that HDMP is a novel NAM of neuronal nAChRs with potent inhibitory activity at α7 nAChR subtype at concentrations ≤ 1μM that are not effective for α4β2 and α3β4 nAChRs.
    Neuropharmacology 11/2010; 59(6):511-7. · 4.11 Impact Factor
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    ABSTRACT: 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.
    Journal of Medicinal Chemistry 11/2010; · 5.61 Impact Factor
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    ABSTRACT: This report describes the discovery that 1-substituted 4-(3-hydroxyphenyl)piperazines are pure opioid receptor antagonists. Compounds in this new series include N-phenylpropyl (3S)-3-methyl-4-(3-hydroxyphenyl)piperazine and (3R)-3-methyl-4-(3-hydroxyphenyl)piperazine, both of which diaplay low nanomolar potencies at μ, δ, and κ receptors and pure antagonist properties in a [(35)S]GTPγS assay.
    ACS Medicinal Chemistry Letters 10/2010; 1(7):365-369. · 3.31 Impact Factor
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    ABSTRACT: Bupropion is an atypical antidepressant that also has utility as a smoking cessation aid. Hydroxybupropions are major metabolites of bupropion and are believed to contribute to antidepressant and perhaps smoking cessation activities. Because bupropion metabolism is more similar in humans and mice than in humans and rats, the present study investigated effects of hydroxybupropion enantiomers in mouse behavioral models measuring various aspects of nicotine dependence. Bupropion and (2S,3S)-hydroxybupropion, but not (2R,3R)-hydroxybupropion, significantly decreased the development of nicotine reward as measured in the conditioned place preference and withdrawal paradigm in mice. Bupropion and both of its metabolites reversed affective and somatic withdrawal signs in nicotine-dependent mice, but the (2S,3S)-hydroxymetabolite had higher potency. Bupropion and (2S,3S)-, but not (2R,3R)-hydroxybupropion, produced partial substitution for nicotine in drug discrimination tests. Our findings support the hypothesis that the effects of bupropion on measures of nicotine dependence reflect actions of bupropion itself, its hydroxymetabolites, or a combination and suggest that the (2S,3S)-hydroxy isomer is the most active principle, making it a potentially better drug candidate for smoking cessation than bupropion.
    Journal of Pharmacology and Experimental Therapeutics 09/2010; 334(3):1087-95. · 3.89 Impact Factor
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    ABSTRACT: Analogs of nantenine were docked into a modeled structure of the human 5-HT(2A) receptor using ICM Pro, GLIDE, and GOLD docking methods. The resultant docking scores were used to correlate with observed in vitro apparent affinity (K(e)) data. The GOLD docking algorithm when used with a homology model of 5-HT(2A), based on a bovine rhodopsin template and built by the program MODELLER, gives results which are most in agreement with the in vitro results. Further analysis of the docking poses among members of a C1 alkyl series of nantenine analogs, indicate that they bind to the receptor in a similar orientation, but differently than nantenine. Besides an important interaction between the protonated nitrogen of the C1 alkyl analogs and residue Asp155, we identified Ser242, Phe234, and Gly238 as key residues responsible for the affinity of these compounds for the 5-HT(2A) receptor. Specifically, the ability of some of these analogs to establish a H-bond with Ser242 and hydrophobic interactions with Phe234 and Gly238 appears to explain their enhanced affinity as compared to nantenine.
    Bioorganic & medicinal chemistry 08/2010; 18(15):5562-75. · 2.82 Impact Factor
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    ABSTRACT: 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 horizontal lineCH-, CH(2), O, S, or SO group was accomplished and used to further characterize the SAR of the compound 3 class of kappa opioid receptor antagonists. All of the compounds showed subnanomolar to low nanomolar K(e) values at the kappa opioid receptor. The most potent compound was 7a, where the amino -NH- group of 3 was replaced by a methylene (-CH(2)-) group. This compound had a K(e) = 0.18 nM and was 37- and 248-fold selective for the kappa relative to the mu and delta opioid receptors, respectively. Similar to compound 3, compound 7a antagonized selective kappa agonist U50,488-induced diuresis after sc administration in rats. In contrast to 3, where kappa antagonist activity lasted for three weeks, compound 7a did not show any kappa antagonist activity after one week.
    Journal of Medicinal Chemistry 07/2010; 53(14):5290-301. · 5.61 Impact Factor
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    ABSTRACT: (-)Nicotine produces antinociceptive effects in rodents. meta-Chlorophenylguanidine (MD-354), an analgesia-enhancing agent, binds at 5-HT(3) and alpha(2)-adrenoceptors and potentiates the antinociceptive effects of an "inactive" dose of clonidine. The present study examined the actions of MD-354 on (-)nicotine-induced antinociception. Mouse tail-flick and other assays were employed. In the tail-flick assay, (-)nicotine (ED(50) = 1.66 mg/kg) but not MD-354 produced dose-related antinociceptive effects. Administered in combination with (-)nicotine (2.5 mg/kg), MD-354 (AD(50) = 3.4 mg/kg) did not potentiate, but effectively antagonized the antinociceptive actions of (-)nicotine. In a mouse hot-plate assay, MD-354 failed to modify (-)nicotine responses. In combination with a locomotor activity-suppressing dose of (-)nicotine, MD-354 (up to 17 mg/kg) failed to antagonize (-)nicotine-induced hypolocomotion. In a rat drug discrimination paradigm using (-)nicotine as training drug, MD-354 produced saline-appropriate responding; in combination with the training dose of (-)nicotine, MD-354 failed to antagonize the nicotine cue. MD-354 selectively antagonizes the antinociceptive actions of (-)nicotine in the tail-flick, but not in the hot-plate assay, or either the motor effects, or discriminative stimulus effects of (-)nicotine. The most parsimonious explanation is that MD-354 might act as a negative allosteric modulator of alpha 7 nACh receptors, and radioligand binding and functional data are provided to support this conclusion.
    Psychopharmacology 07/2010; 210(4):547-57. · 4.06 Impact Factor
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    ABSTRACT: To create potentially superior aids to smoking cessation and/or antidepressants and to elucidate bupropion's possible mechanisms of action(s), 23 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 alpha4beta2-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 alpha4beta2-nAChR can potentially be new pharmacotherapeutics for treatment of nicotine dependence.
    Journal of Medicinal Chemistry 06/2010; 53(12):4731-48. · 5.61 Impact Factor
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    ABSTRACT: In 1992, John Daly et al. reported the isolation and structure determination of epibatidine. Epibatidine's unique structure and its potent nicotinic agonist activity have had a tremendous impact on nicotine receptor research. This research has led to a better understanding of the nicotinic acetylcholine receptor (nAChR) pharmacophore and to epibatidine analogues with potential as pharmacotherapies for treating various CNS disorders. In this study, we report the synthesis, receptor binding ([(3)H]epibatidine and [(125)I]iodoMLA), and in vivo pharmacological properties (mouse tail flick, hot plate, hypothermia, and spontaneous activity) of a series of 3'-(substituted phenyl)epibatidine analogues (5a-m). Results from these studies have added to the understanding of the nAChR pharmacophore and led to nicotinic partial agonists that may have potential for smoking cessation. All the analogues had affinities for the alpha4beta2 nAChR similar to epibatidine (1). 3'-(3-Dimethylaminophenyl)epibatidine (5m) has a nicotinic partial agonist pharmacological profile similar to the smoking cessation drug varenicline. Other analogues are partial agonists with varying degrees of nicotinic functional agonist and antagonist activity. 3'-(3-Aminophenyl)epibatidine (5j) is a more potent functional agonist and antagonist in all tests than varenicline. 3'-(3-Fluorophenyl)epibatidine and 3'-(3-chlorophenyl)epibatidine (5c and 5e) are more potent than varenicline when tested as agonists in four pharmacological tests and antagonists when evaluated against nicotine in the analgesia hot-plate test.
    Journal of Natural Products 03/2010; 73(3):306-12. · 3.29 Impact Factor

Publication Stats

1k Citations
382.78 Total Impact Points

Institutions

  • 1997–2014
    • Research Triangle Park Laboratories, Inc.
      Raleigh, North Carolina, United States
  • 2011
    • City University of New York - Hunter College
      • Department of Chemistry
      Manhattan, NY, United States
  • 2010
    • Barrow Neurological Institute
      • Division of Neurobiology
      Phoenix, AZ, United States
  • 2009–2010
    • CUNY Graduate Center
      New York City, New York, United States
  • 2006–2010
    • RTI International
      • Division of Organic and Medicinal Chemistry
      Durham, North Carolina, United States
  • 2006–2007
    • University of Iowa
      • College of Pharmacy
      Iowa City, IA, United States
  • 2004
    • Virginia Commonwealth University
      • Department of Pharmacology and Toxicology
      Richmond, VA, United States
  • 1988–1991
    • Duke University Medical Center
      • Department of Pharmacology and Cancer Biology
      Durham, NC, United States