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1.  Synthesis, Binding Affinity, and Functional In Vitro Activity of 3-Benzylaminomorphinan and 3-Benzylaminomorphine Ligands at Opioid Receptors 
Journal of Medicinal Chemistry  2012;55(8):3878-3890.
A series of 3-benzylamino-3-desoxymorphinan (I) and 3-benzylamino-3-desoxymorphine (II) derivatives were synthesized and evaluated for their binding affinities and functional activity data are presented at MOR, KOR, and DOR. Some of these ligands were found to have high binding affinity at MOR and KOR, and displayed increased selectivity at MOR over KOR and DOR compared to butorphan or cyclorphan. The most selective compound, 3-(3′-hydroxybenzyl)amino-17-methylmorphinan (4g) (24-fold MOR to KOR and 1700-fold MOR to DOR) also showed high binding affinity (0.42 nM to MOR), and was a full agonist in the [35S]GTPγS binding assay. 2-(3′-Hydroxybenzyl)amino-17-cyclopropylmethylmorphinan (17) was found to be a KOR-selective ligand (150-fold over MOR and >10,000-fold over the DORs). Most 3-benzylaminomorphinan derivatives were partial agonists at MOR and full agonists at KOR in the [35S]GTPγS binding assay.
doi:10.1021/jm3001086
PMCID: PMC3375359  PMID: 22439881
2.  Sulfur-Containing 1,3-Dialkylxanthine Derivatives as Selective Antagonists at A1-Adenosine Receptors 
Journal of medicinal chemistry  1989;32(8):1873-1879.
Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [[3H]-N6-(phenylisopropyl) adenosine as radioligand] or striatum [[3H]-5′-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was >740-fold A1 selective.
PMCID: PMC3479653  PMID: 2754711
3.  Pharmacological Properties of Bivalent Ligands Containing Butorphan Linked to Nalbuphine, Naltrexone and Naloxone at μ, δ and κ Opioid Receptors 
Journal of Medicinal Chemistry  2007;50(9):2254-2258.
Investigation of bivalent ligands at μ, δ and κ opioid receptors is now focused on the preparation of ligands containing κ agonist and μ agonist/antagonist pharmacophores at one end joined by a linking chain containing the μ antagonists pharmacophores (naltrexone, naloxone or nalbuphine) at the other end. These ligands were evaluated in-vitro by their binding affinity at μ, δ and κ opioid receptors and their relative efficacy in the [35S]GTPγS assay.
Ligands 6-8 displayed better or the same affinity at κ and μ receptors compared to the monovalent ligands 1-5. Ligands 6-8 generally showed reduced affinity at δ receptor compared to the monovalent ligands 1-5. Functional assays showed that the ligand 6 was a κ agonist/antagonist and μ antagonist whereas ligands 7 and 8 were κ agonists and μ agonists/antagonists.
doi:10.1021/jm061327z
PMCID: PMC3357624  PMID: 17407276
4.  Synthesis and Binding Affinity of Novel Mono- and Bivalent Morphinan Ligands for κ, μ and δ Opioid Receptors 
Bioorganic & medicinal chemistry  2011;19(9):2808-2816.
A novel series of homo- and heterodimeric ligands containing κ/μ agonist and μ agonist/antagonist pharmacophores joined by a 10-carbon ester linker chain were synthesized and evaluated for their in vitro binding affinity at κ, μ, and δ opioid receptors and their functional activities were determined at κ and μ receptors in [35S]GTPγS functional assays. Most of these compounds had high binding affinity at μ and κ receptors (Ki values less than 1 nM). Compound 15b, which contains butorphan (1) at one end of linking chain and butorphanol (5) at the other end, was the most potent ligand in this series with binding affinity Ki values of 0.089 nM at the μ receptor and 0.073 nM at the κ receptor. All of the morphinan-derived ligands were found to be partial κ and μ agonists; ATPM-derived ligands 12 and 11 were found to be full κ agonists and partial μ agonists.
doi:10.1016/j.bmc.2011.03.052
PMCID: PMC3095849  PMID: 21482470
5.  Aminothiazolomorphinans with Mixed Kappa and Mu Opioid Activitya 
Journal of medicinal chemistry  2011;54(6):1903-1913.
A series of N-substituted and N′-substituted aminothiazole-derived morphinans (5) were synthesized for expanding the structure-activity relationships of aminothiazolo-morphinans. Although their affinities were somewhat lower than their prototype aminothiazolo-N-cyclopropylmorphinan (3), 3-aminothiazole derivatives of cyclorphan (1) containing a primary amino group displayed high affinity and selectivity at the κ and μ opioid receptors. [35S]GTPγS binding assays showed that the aminothiazolomorphinans were κ agonists with mixed agonist and antagonist activity at the μ opioid receptor. These novel N′-monosubstituted aminothiazole-derived morphinans may be valuable for the development of drug abuse medications.
doi:10.1021/jm101542c
PMCID: PMC3068608  PMID: 21351746
6.  Synthesis and Biological Evaluation of N-Fluoroalkyl and 2-Fluoroalkoxy Substituted Aporphines: Potential PET Ligands for Dopamine D2 Receptors 
ACS medicinal chemistry letters  2011;2(3):189-194.
The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D2 receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for development as potential PET ligands.
doi:10.1021/ml1001689
PMCID: PMC3110009  PMID: 21666830
aporphine; D2 agonist; neurological disorders; positron emission tomography; dopamine receptors
7.  Opioid Bifunctional Ligands from Morphine and the Opioid Pharmacophore Dmt-Tic 
Bifunctional ligands containing an ester linkage between morphine and the δ-selective pharmacophore Dmt-Tic were synthesized, and their binding affinity and functional bioactivity at the μ, δ and κ opioid receptors determined. Bifunctional ligands containing or not a spacer of β-alanine between the two pharmacophores lose the μ agonism deriving from morphine becoming partial μ agonists 4 or μ antagonists 5. Partial κ agonism is evidenced only for compound 4. Finally, both compounds showed potent δ antagonism.
doi:10.1016/j.ejmech.2010.12.001
PMCID: PMC3035428  PMID: 21216504
8.  Rapid access to morphinones: removal of 4, 5-ether bridge with Pd-catalyzed triflate reduction 
Tetrahedron letters  2010;51(17):2359-2361.
A new synthetic method for the removal of the 4, 5-bridged ether moiety of several opioids has been developed. This process offers a faster, simpler synthetic route to obtain the morphinone scaffold in high yields without the need for protection of the ketone moiety.
doi:10.1016/j.tetlet.2010.02.146
PMCID: PMC2872489  PMID: 20495617
morphinone; opioid; 4, 5-ether bridge; triflate reduction
9.  Effect of Linker Substitution on the Binding of Butorphan Univalent and Bivalent Ligands to Opioid Receptors 
A series of bivalent hydroxy ether butorphan ligands were prepared and their binding affinities at the opioid receptors determined. Addition of a hydroxy group to a hydrocarbon chain can potentiate binding affinity up to 27 and 86 fold at the mu and kappa opioid receptors, respectively. Two bivalent ligands with sub-nanomolar binding affinity at the mu and kappa opioid receptors were discovered.
doi:10.1016/j.bmcl.2010.01.101
PMCID: PMC2834170  PMID: 20144870
10.  Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore 
ACS chemical neuroscience  2010;1(2):155-164.
Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH3, partially −NO2, inactive -NH2) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA2 = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.
doi:10.1021/cn900025j
PMCID: PMC2843921  PMID: 20352071
11.  Evolution of the Bifunctional Lead μ Agonist/δ Antagonist Containing the 2′,6′-Dimethyl-l-tyrosine−1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Dmt−Tic) Opioid Pharmacophore 
ACS Chemical Neuroscience  2009;1(2):155-164.
Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist/δ antagonist, H-Dmt-Tic-Gly-NH-Bzl (Dmt = 2′,6′-dimethyl-l-tyrosine, Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Bzl = benzyl). Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (−Cl, −CH3, partially −NO2, inactive −NH2) was found to give a more potent μ agonist/antagonist effect associated with a relatively unmodified δ antagonist activity (pA2 = 8.28−9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly d-Tic2, considered as a wrong opioid message now, inserted into the reference compound in lieu of l-Tic provided a μ agonist/δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph; Ph = phenyl) and was endowed with the same pharmacological profile.
doi:10.1021/cn900025j
PMCID: PMC2843921  PMID: 20352071
Bifunctional opioids; Dmt−Tic pharmacophore; opioid peptides; opioid receptors, angiogenesis, tolerance
12.  Synthesis and Opioid Receptor Binding Affinities of 2-Substituted and 3-Aminomorphinans: Ligands for mu, kappa and delta Opioid Receptors 
The phenolic group of the potent μ and κ opioid morphinan agonist/antagonists cyclorphan and butorphan was replaced by phenylamino and benzylamino groups including compounds with p-substituents in the benzene ring. These compounds are highly potent μ and κ ligands, e. g. p-methoxyphenylaminocyclorphan showing a Ki of 0.026 nM at the mu and a Ki of 0.03 nM at the kappa receptor. Phenyl carbamates and phenylureas were synthesized and investigated. Selective o-formylation of butorphan and levorphanol was achieved. This reaction opened the way to a large set of 2-substituted 3-hydroxymorphinans, including 2-hydroxymethyl-, 2-aminomethyl-, and N-substituted 2-aminomethyl-3-hydroxymorphinans. Bivalent ligands bridged in the 2-position were also synthesized and connected with secondary and tertiary aminomethyl groups, amide bonds or hydroxymethylene groups, respectively. Although most of the 2-substituted morphinans showed considerably lower affinities compared to their parent compounds, the bivalent ligand approach led to significantly higher affinities compared to the univalent aminomethylmorphinans.
doi:10.1021/jm9013482
PMCID: PMC2814335  PMID: 19928862
13.  Univalent and Bivalent Ligands of Butorphan: Characteristics of the Linking Chain determine the Affinity and Potency of Such Opioid Ligands† 
Journal of medicinal chemistry  2009;52(23):7389-7396.
Bivalent morphinan compounds containing ester linkers were synthesized and their binding affinities at the μ, δ, and κ opioid receptors determined. Addition of methyl groups adjacent to the hydrolytically labile ester linkage increased stability while only partially affecting binding affinity. The resulting bivalent ligands with optimized spacer-length and structure show potent binding profiles with the most potent compound (4b) having Ki values of 0.47 nM for both the μ and κ opioid receptors, and 4a having Ki values of 0.95 and 0.62 nM for the μ and κ receptors, respectively. Both 4a and 4b were partial agonists at the κ and μ receptors in the [35S]GTPγS binding assay.
doi:10.1021/jm900379p
PMCID: PMC2788666  PMID: 19634902
14.  In Vivo Characterization of (−)(−)MCL-144 and (+)(−)MCL-193: Isomeric, Bivalent Ligands with Mu/Kappa Agonist Properties 
Neurochemical research  2008;33(10):2142-2150.
Once opioid receptor dimers were postulated, a goal has been to synthesize and screen novel opioids, with the hope of furthering our knowledge of the structure-activity relationship of opioid ligands with the opioid receptors. The aim of the current study was to address whether two isomeric bivalent ligands would have pharmacological differences after central administration, in vivo. The two compounds, (−) bis(N-cyclobutylmethyl-morphinan-3-yl) sebacoylate dihydrochloride (MCL-144) and 1-((+)N-cyclobutylmethylmorphinan-3-yl)-10-((−) N-cyclobutylmethylmorphinan-3-yl)sebacolyate (MCL-193) are each linked by a 10-carbon chain ester. The active (−) enantiomer for both ligands is 3-hydroxy-N-cyclobutylmethyl morphinan ((−)MCL-101), a N-cyclobutylmethyl analogue of cyclorphan (1). MCL-144 contains two active levo rotatory (−)(−) pharmacophores, while MCL-193 contains one active (−) and one inactive (+) pharmacophore of MCL-101. In vitro analysis demonstrated that all three compounds, (−)(−) MCL-144, (+)(−) MCL-193 and (−)MCL-101 were κ agonists and μ partial agonists. (−)(−)MCL-144 and (−)MCL-101 had much higher affinity for both the μ and κ opioid receptors compared to (+)(−)MCL-193. In vivo, (−)(−)MCL-144 and (+)(−)MCL-193 produced full dose-response curves, in the 55°C tail-flick test, with each compound having an ED50 value of 3.0 nmol after intracerebroventricular (i.c.v.) administration. The analgesic properties of both compounds were antagonized by the μ-selective antagonist, β-funaltrexamine and the κ-selective antagonist nor-binaltorphimine. Concomitant, i.c.v., administration of either (−)(−)MCL-144 or (+)(−)MCL-193 with morphine, did not significantly antagonize morphine-induced antinociception at any dose tested. In antinociceptive tests, (−)(−)MCL-144 and (+)(−)MCL-193 had the same pharmacological properties, demonstrating that having two active pharmacophores separated by a 10-carbon spacer group did not increase the antinociceptive efficacy of the compound. Additionally, it was also of interest to compare (−)(−)MCL-145 and (−)(−)MCL-144, as the only difference between these bivalent ligands is the spacer region connecting the two pharmacophores, yet (−)(−)MCL-145 produced an ED50 value 10-fold lower than (−)(−)MCL-144 (ED50 values = 0.3 nmol and 3.0 nmol, respectively).
doi:10.1007/s11064-008-9752-3
PMCID: PMC2574661  PMID: 18528756
opioid dimers; mu opioid; partial agonist; enantiomers
15.  Synthesis and Pharmacological Evaluation of Hydrophobic Esters and Ethers of Butorphanol at Opioid Receptors 
We synthesized several hydrophobic esters and ethers of butorphanol and assessed their affinities at opioid receptors in CHO cell membranes. Tested compounds displayed moderate to high affinities to the mu and kappa receptors. The findings accord with previous evidence of a lipophilic binding pocket in the opioid receptors that can be accessed to afford good binding affinity without the need for a phenolic hydrogen-bond donor group. The most potent (Ki = 61 pM at μ and 48 pM at κ) novel agent was (-)-N-cyclobutylmethylmorphinan-3-yl-14-ol phenoxyacetate (4d).
doi:10.1016/j.bmcl.2008.07.054
PMCID: PMC2745115  PMID: 18674902
16.  In-vitro Investigation of Oxazol and Urea Analogues of Morphinan at Opioid Receptors 
Bioorganic & medicinal chemistry  2007;15(12):4106-4112.
A series of 2-amino-oxazole (7 & 8) analogs and 2-one-oxazole analogs (9 &10) were synthesized from cyclorphan (1) or butorphan (2) and evaluated in-vitro by their binding affinity at μ, δ and κ opioid receptors and compared with their 2-aminothiozole analogs 5 & 6. Ligands 7–10 showed decreased affinities at κ and μ receptors.
Urea analogues (11–14) were also prepared from 2-aminocyclorphan (3) or 2-aminobutorphan (4) and evaluated in-vitro by their binding affinity at μ, δ and κ opioid receptors. The urea derived opioids retained their affinities at μ receptors while showing increased affinities at δ receptors and decreased affinities at κ receptors. Functional activities of these compounds were measured in the [35S]GTPγS binding assay, illustrating that all of these ligands were κ agonists. At the μ receptor, compounds 11 and 12 were μ agonist/antagonists.
doi:10.1016/j.bmc.2007.03.076
PMCID: PMC2706089  PMID: 17433695
Morphinan; Urea; Oxazol; Opioid
17.  Arylbenzazepines Are Potent Modulators for the Delayed Rectifier K+ Channel: A Potential Mechanism for Their Neuroprotective Effects 
PLoS ONE  2009;4(6):e5811.
(±) SKF83959, like many other arylbenzazepines, elicits powerful neuroprotection in vitro and in vivo. The neuroprotective action of the compound was found to partially depend on its D1-like dopamine receptor agonistic activity. The precise mechanism for the (±) SKF83959-mediated neuroprotection remains elusive. We report here that (±) SKF83959 is a potent blocker for delayed rectifier K+ channel. (±) SKF83959 inhibited the delayed rectifier K+ current (IK) dose-dependently in rat hippocampal neurons. The IC50 value for inhibition of IK was 41.9±2.3 µM (Hill coefficient = 1.81±0.13, n = 6), whereas that for inhibition of IA was 307.9±38.5 µM (Hill coefficient = 1.37±0.08, n = 6). Thus, (±) SKF83959 is 7.3-fold more potent in suppressing IK than IA. Moreover, the inhibition of IK by (±) SKF83959 was voltage-dependent and not related to dopamine receptors. The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (±) SKF83959 with the K+ channel. The intracellular application of (±) SKF83959 had no effects of on IK, indicating that the compound most likely acts at the outer mouth of the pore of K+ channel. We also tested the enantiomers of (±) SKF83959, R-(+) SKF83959 (MCL-201), and S-(−) SKF83959 (MCL-202), as well as SKF38393; all these compounds inhibited IK. However, (±) SKF83959, at either 0.1 or 1 mM, exhibited the strongest inhibition on the currents among all tested drug. The present findings not only revealed a new potent blocker of IK , but also provided a novel mechanism for the neuroprotective action of arylbenzazepines such as (±) SKF83959.
doi:10.1371/journal.pone.0005811
PMCID: PMC2690691  PMID: 19503734
18.  Behavioral effects of the R-(+)- and S-(−) enantiomers of the D1-like partial receptor agonist SKF 83959 in monkeys 
European journal of pharmacology  2006;558(1-3):98-106.
Dopamine D1-like partial receptor agonists such as SKF 83959 have been proposed as potential candidates for the treatment of cocaine addiction. The present studies were conducted to further characterize SKF 83959 by pharmacologically evaluating effects of its R-(+)- and S-(−) enantiomers, MCL 202 and MCL 201, respectively, on overt behavior (eye blinking) and schedule-controlled performance in squirrel monkeys. MCL 202, like the D1 full receptor agonist SKF 82958, produced dose related increases in eye blinking and decreases in rates of fixed-ratio responding. However, the magnitude of effects of MCL 202 on eye blinking was less than observed with SKF 82958. In contrast to the effects of its R-(+) enantiomer, MCL 201 was relatively devoid of behavioral activity up to doses that were approximately 10-fold greater than MCL 202. Pretreatment with the selective D1-like receptor antagonist SCH 39166 dose-dependently antagonized increases in eye blinking produced by MCL 202, confirming the involvement of D1 mechanisms in its effects. A dose-ratio analysis of the antagonism of effects of MCL 202 by SCH 39166 revealed an apparent pA2 value of 7.675 with a slope of −0.78 ± 0.04. In further studies, pretreatment with MCL 202 antagonized the effects of SKF 82958 on eye blinking and, like SCH 39166, schedule-controlled behavior in a dose-related manner. A dose-ratio analysis of the antagonist effects of MCL 202 on the SKF 82958-induced increases in eye blinking revealed ratios of 2.7, 4.8 and 31.1 for 0.1, 0.3 and 1.0 mg/kg dose of the antagonist, respectively, indicative of a significant change in the potency of SKF 82958. These results suggest that MCL 202, like its parent compound SKF 83959, has both D1 receptor-mediated agonist and antagonist properties, consistent with its characterization as a partial agonist at the D1-like receptor. In addition, the inactivity of MCL 201, the S-(−)-enantiomer, suggests that the behavioral effects of SKF 83959 can be attributed primarily to the activity of its R-(+)-enantiomer.
doi:10.1016/j.ejphar.2006.11.042
PMCID: PMC2447824  PMID: 17207791
Dopamine D1-like receptors; Enantiomers of SKF 83959; Partial agonist; Eye blinking; Schedule-controlled behavior; SKF 82958; Squirrel monkeys
19.  New Opioid Designed Multiple Ligand from Dmt-Tic and Morphinan Pharmacophores 
Journal of medicinal chemistry  2006;49(18):5640-5643.
Here we report the facile synthesis of a designed multi-pharmacophore ligand derived from the linkage of a delta selective peptide antagonist (Dmt-Tic) and a mu / kappa morphinan agonist butorphan (MCL 101) through a two methylene spacer. The new compound MCL 450 maintains the same characteristics as the two reference compounds. MCL 450 represents a useful starting point for the synthesis of other multiple opioid ligands endowed with analgesic properties with low tolerance and dependence.
doi:10.1021/jm0605785
PMCID: PMC2435260  PMID: 16942040
20.  High Affinity of Carbamate Analogues of Morphinan atOpioid Receptors 
A series of carbamate analogues were synthesized from levorphanol (1a), cyclorphan (2a) or butorphan (3a) and evaluated in vitro by their binding affinity at μ, δ and κ opioid receptors. Functional activities of these compounds were measured in the [35S]GTPγS binding assay. Phenyl carbamate derivatives 2d and 3d showed the highest binding affinity for κ receptor (Ki = 0.046 nM and 0.051nM) and for μ receptor (Ki = 0.11 nM and 0.12 nM). Compound 1c showed the highest μ selectivity. The preliminary assay for agonist and antagonist properties of these ligands in stimulating [35S]GTPγS binding mediated by the κ opioid receptor illustrated that all of these ligands were κ agonists. At the μ receptor, compounds 1b, 1c, 2b and 3b were agonists, while compounds 2c, 2d, 2e, 3c, 3d and 3e were μ agonists/antagonists.
doi:10.1016/j.bmcl.2007.01.03
PMCID: PMC1853345  PMID: 17276685
Morphinan; Carbamate; Opioid; Receptors

Results 1-20 (20)