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1.
Molecules ; 25(12)2020 Jun 26.
Article in English | MEDLINE | ID: mdl-32604891

ABSTRACT

A series of benzene ring substituted ketamine N-alkyl esters were prepared from the corresponding substituted norketamines. Few of the latter have been reported since they have not been generally accessible via known routes. We report a new general route to many of these norketamines via the Neber (oxime to α-aminoketone) rearrangement of readily available substituted 2-phenycyclohexanones. We explored the use of the substituents Cl, Me, OMe, CF3, and OCF3, with a wide range of lipophilic and electronic properties, at all available benzene ring positions. The 2- and 3-substituted compounds were generally more active than 4-substituted compounds. The most generally acceptable substituent was Cl, while the powerful electron-withdrawing substituents CF3 and OCF3 provided fewer effective analogues.


Subject(s)
Analgesics/chemical synthesis , Anesthetics/chemical synthesis , Cyclohexanes/chemical synthesis , Ketamine/analogs & derivatives , Analgesics/administration & dosage , Analgesics/chemistry , Analgesics/pharmacology , Anesthetics/administration & dosage , Anesthetics/chemistry , Anesthetics/pharmacology , Animals , Cyclohexanes/administration & dosage , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Down-Regulation , Esters/chemistry , Inhibitory Concentration 50 , Ketamine/chemistry , Molecular Structure , Oximes/chemistry , Rats , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Structure-Activity Relationship
2.
Mini Rev Med Chem ; 14(4): 355-69, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24678879
3.
Anesth Analg ; 113(2): 387-9, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21642612

ABSTRACT

On December 30, 2010, Ross C. Terrell, PhD, died. With his passing at age 85, we lost one of the pioneers of modern anesthesia. Terrell synthesized most of the inhalation anesthetics used today, including desflurane, enflurane, isoflurane, and sevoflurane.


Subject(s)
Anesthesiology/history , Anesthetics/history , Anesthetics/chemical synthesis , Ethers/history , History, 20th Century , New York
4.
Curr Med Chem ; 17(36): 4538-50, 2010.
Article in English | MEDLINE | ID: mdl-21062252

ABSTRACT

The development of neuroactive drugs is a time consuming procedure. Candidate drugs must be run through a battery of tests, including receptor studies and behavioural tests on animals. As a rule, numerous substances with promising properties as assessed in receptor studies must be eliminated from the development pipeline in advanced test phases because of unforeseen problems like intolerable side-effects or unsatisfactory performance in the whole organism. Clearly, test systems of intermediate complexity would alleviate this inefficiency. In this review, we propose cultured organotypic brain slices as model systems that could bridge the 'interpolation gap' between receptors and the brain, with a focus on the development of new general anaesthetics with lesser side effects. General anaesthesia is based on the modulation of neurotransmitter receptors and other conductances located on neurons in diverse brain regions, including cerebral cortex and spinal cord. It is well known that different components of general anaesthesia, e.g. hypnosis and immobility, are produced by the depression of neuronal activity in distinct brain regions. The ventral horn of the spinal cord is an important structure for the induction of immobility. Thus, the potentially immobilizing effects of a newly designed drug can be estimated from its depressant effect on neuronal network activity in cultured spinal slices. A drug's sedative and hypnotic potential can be examined in cortical cultures. Combined with genetically engineered mice, this approach can point to receptor subtypes most relevant to the drug's intended net effect and in return can help in the design of more selective drugs. In conclusion, the use of organotypic cultures permits predictions of neuroactive properties of newly designed drugs on an intermediate level, and should therefore open up avenues for a more creative and economic drug development process.


Subject(s)
Anesthetics/pharmacology , Brain/drug effects , Neural Conduction/drug effects , Receptors, Neurotransmitter/drug effects , Anesthetics/chemical synthesis , Anesthetics/chemistry , Animals , Brain/metabolism , Drug Design , Humans , Organ Culture Techniques
6.
J Clin Anesth ; 20(7): 556-9, 2008 Nov.
Article in English | MEDLINE | ID: mdl-19019661

ABSTRACT

Ethanol was an early anesthetic, and chemists transformed it into better ones. Hypnotic/anesthetic/analgesic molecules prepared from ethanol include barbiturates, benzocaine, chloral hydrate, chloroform, diethyl ether, ethyl chloride, ethylene, etomidate, meperidine, paraldehyde, phenacetin, procaine, tribromoethanol, and urethane. Ethanol was sometimes mixed deliberately with the other anesthetics, and John Snow's inhaled amylene came from the "fusel oil" fraction of rotgut whisky.


Subject(s)
Anesthetics/chemical synthesis , Central Nervous System Depressants/chemistry , Chloroform/chemical synthesis , Ethanol/chemistry , Anesthesiology/history , Anesthetics/history , Barbiturates/chemical synthesis , Barbiturates/history , Benzocaine/chemical synthesis , Benzocaine/history , Central Nervous System Depressants/history , Central Nervous System Depressants/metabolism , Chloroform/history , Ethanol/history , Ethanol/metabolism , History, 18th Century , History, 19th Century , History, 20th Century
8.
Clin Pharmacol Ther ; 84(1): 144-8, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18449184

ABSTRACT

The ability to render patients insensible and amnesic to remarkably invasive procedures that are uncomfortable to watch, let alone experience, has been rightly designated as one of the greatest medical discoveries of all time. General anesthesia, introduced formally in the mid-nineteenth century, is now delivered to approximately 40 million patients every year in the United States alone. Given its central role in health care, it is indeed extraordinary how poorly we understand anesthesia and anesthetics. In fact, definitions are at best operational and convey little understanding of the underlying neurobiology, while the hypothetical mechanisms are surprisingly superficial. Worse, there is growing concern that the anesthetic drugs in current use, especially the inhaled anesthetics, have durable adverse effects on cognition.


Subject(s)
Anesthetics/chemical synthesis , Anesthetics/pharmacokinetics , Drug Design , Research/trends , Technology, Pharmaceutical/trends , Anesthetics/pharmacology , Animals , Humans
9.
J Med Chem ; 51(5): 1309-18, 2008 Mar 13.
Article in English | MEDLINE | ID: mdl-18275132

ABSTRACT

Although the structural features of binding sites for neuroactive steroids on gamma-aminobutryic acid type A (GABA A) receptors are still largely unknown, structure-activity studies have established a pharmacophore for potent enhancement of GABA A receptor function by neuroactive steroids. This pharmacophore emphasizes the importance of the position and stereochemistry of hydrogen-bonding groups on the steroid. However, the importance of the steroid ring system in mediating hydrophobic interactions with the GABA A receptor is unclear. We have taken the cyclopenta[ b]phenanthrene (tetracyclic compounds with a nonlinear ring system different from that of steroids) and cyclopenta[ b]anthracene (tetracyclic molecules with a linear 6-6-6-5 carbocyclic ring system) ring systems and properly substituted them to satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids. We have found these cyclopenta[ b]phenanthrene and cyclopenta[ b]anthracene analogues to have potent activity at the GABA A receptor, rivaling that of the most potent steroid modulators. Single-channel analysis of electrophysiological data indicates that similarly substituted analogues in the different ring systems affect the kinetic components of macroscopic currents in different ways. Mutations to the hydrogen bonding amino acids at the putative steroid binding site (alpha1Q241L mutation and alpha1N407A/Y410F double mutation) produce similar effects on macroscopic current amplitude by the different ring system analogues suggesting that the different kinetic effects are explained by the precise interactions of each analogue with the same binding site(s).


Subject(s)
Anesthetics/chemical synthesis , Anthracenes/chemical synthesis , GABA Modulators/chemical synthesis , Phenanthrenes/chemical synthesis , Receptors, GABA-A/physiology , Anesthetics/chemistry , Anesthetics/pharmacology , Animals , Anthracenes/chemistry , Anthracenes/pharmacology , Binding Sites , Brain/metabolism , Cell Line , GABA Modulators/chemistry , GABA Modulators/pharmacology , Humans , In Vitro Techniques , Larva , Models, Molecular , Mutation , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , Radioligand Assay , Rats , Receptors, GABA-A/genetics , Stereoisomerism , Steroids/pharmacology , Structure-Activity Relationship , Xenopus laevis
10.
Cir. plást. ibero-latinoam ; 31(4): 217-224, oct.-dic. 2005. tab
Article in Es | IBECS | ID: ibc-050626

ABSTRACT

Un gran número de intervenciones de cirugía plástica se practican con técnicas de anestesia local. Los anestésicos locales (AL) son fármacos fiables y seguros aunque su uso no está exento de riesgos. El objetivo del presente estudio es describir de manera somera las principales características farmacológicas de los AL (destacando aquellos aspectos que pueden resultar más interesantes para el cirujano plástico) con el fin de optimizar sus indicaciones y prevenir las aparición de complicaciones. Los AL más utilizados son de tipo amida. El conocimiento de su mecanismo de acción así como de algunas de sus propiedades (duración, efecto vasoconstrictor, toxicidad) es indispensable a la hora de elegir el AL idóneo para cada procedimiento. También resulta importante saber qué factores no farmacológicos influyen en la acción delos AL (dosis administrada, lugar de inyección y medidas antiálgicas de inyección) para optimizar su uso; en este mismo sentido, la adición de aditivos (bicarbonato y vasoconstrictores) puede colaborara disminuir la latencia y la toxicidad así como a mejorar la duración y la calidad del efecto. El uso de adrenalina en partes (..) (AU)


A large number of Plastic Surgery procedures are performed using local anesthesia techniques. Local anesthetics (LA) are safe and reliable drugs although its use is not free of risks. The goal of this work is to describe concisely the main pharmacologycal features of LA (emphasizing the major interest characteristics for plastic surgeons) in order to improve their usage and prevent complications. Amides are the most frequently used LA. Acorrect understanding of their pharmacokinetics (duration, vasoconstricting effect, toxicity) is essential to choose a suitable LA for each procedure. It is also important to know what non-pharmacologic factors influence anesthetic activity (dosage of LA administered, site of injection, measures to reduce injection pain); in this respect, the use of additives (sodium bicarbonate and vasoconstrictors) may decrease the time for anesthesia onset and toxicity and improve the depth and duration of anesthesia. Adrenaline usage in anatomical areas with end arteries (..) (AU)


Subject(s)
Anesthetics, Local/therapeutic use , Surgery, Plastic/methods , Anesthetics, Local/pharmacology , Lidocaine/therapeutic use , Surgery, Plastic/trends , Lidocaine/pharmacology , Mepivacaine/therapeutic use , Prilocaine/therapeutic use , Bupivacaine/therapeutic use , Liposomes/therapeutic use , Anesthetics/adverse effects , Anesthetics/chemistry , Anesthetics/chemical synthesis , Anesthetics
11.
J Med Chem ; 48(8): 3051-9, 2005 Apr 21.
Article in English | MEDLINE | ID: mdl-15828844

ABSTRACT

The planar 5alpha-reduced steroid (3alpha,5alpha)-3-hydroxypregnan-20-one and the nonplanar 5beta-reduced steroid (3alpha,5beta)-3-hydroxypregnan-20-one act at GABA(A) receptors to induce general anesthesia. The structural features of the binding sites for these anesthetic steroids on GABA(A) receptors have not been determined. To determine how structural modifications at the steroid C-6 and C-7 positions effect the actions of these anesthetic steroids, an axial or equatorial methyl group was introduced at these positions. The analogues were evaluated (1) in [(35)S]-tert-butylbicyclophosphorothionate binding experiments, (2) in electrophysiological experiments using rat alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes, and (3) as tadpole anesthetics. The effects of methyl group substitution in the 5alpha- and 5beta-reduced series of compounds were strikingly similar. In both series, a 6beta-Me group gave compounds with actions similar to or greater than those of the parent steroids. A 6alpha-, 7beta- or 7alpha-Me substituent resulted in reduced potency for inhibition of radioligand binding, GABA(A) receptor modulation and tadpole anesthesia. Because of the similar effects of methyl group substitution in the two series of compounds and previous results from other studies showing that structural modifications in the steroid D ring/side chain region produce similar effects regardless of the stereochemistry of the A,B-ring fusion, we propose that either the 3alpha-hydroxyl groups of planar and nonplanar anesthetic steroids hydrogen bond to different amino acids on GABA(A) receptors or that this critical hydrogen bonding group interacts with membrane lipids instead of the receptor.


Subject(s)
Anesthetics/chemical synthesis , GABA Modulators/chemical synthesis , Pregnanolone/chemical synthesis , Receptors, GABA-A/drug effects , Anesthetics/chemistry , Anesthetics/pharmacology , Animals , Binding Sites , Binding, Competitive , Brain/metabolism , Electrophysiology , Female , GABA Modulators/chemistry , GABA Modulators/pharmacology , In Vitro Techniques , Larva , Models, Molecular , Oocytes/drug effects , Oocytes/physiology , Pregnanolone/chemistry , Pregnanolone/pharmacology , Radioligand Assay , Rats , Receptors, GABA-A/physiology , Reflex/drug effects , Stereoisomerism , Structure-Activity Relationship , Xenopus laevis
13.
J Med Chem ; 46(25): 5334-48, 2003 Dec 04.
Article in English | MEDLINE | ID: mdl-14640542

ABSTRACT

The hydrogen-bond-acceptor properties of the carbonyl moiety in the 17beta-acetyl group on the D-ring of the anesthetic steroids (3alpha,5alpha)- and (3alpha,5beta)-3-hydroxypregan-20-one form an important part of the anesthetic steroid pharmacophore. 13,24-Cyclo-18,21-dinorcholanes containing a ketone or conjugated ketone group at C-20, C-22, C-23, or C-24 were prepared as conformationally constrained analogues of these anesthetic steroids and were used to probe for alternate locations for the D-ring hydrogen-bond-accepting carbonyl group. The analogues were evaluated (1). in [(35)S]-tert-butylbicyclophosphorothionate binding experiments, (2). in electrophysiological experiments using rat alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes, and (3). as tadpole anesthetics. In the binding assay, the relative order of potencies for the analogues in the 5alpha- and 5beta-series is identical. For the ketones, the order is 24-one >or= 23-one > 20-one > 22-one. Likewise, for the enones, the order is delta(22)-24-one > delta(20(22))-23-one > delta(22)-20-one > delta(23)-22-one. Similar relative orders of potencies are also found in the other two bioassays. The activities of the 24-one and delta(22)-24-one compounds were expected to be very low, because the carbonyl group in these compounds is located over the steroid C-ring and oriented toward C-8. Instead, these compounds have the highest activities in their respective series, with the delta(22)-24-one compounds having activities comparable to those of the reference anesthetic steroids. The electrophysiology results obtained with the 24-oxo-cyclosteroids suggest that rat alpha(1)beta(2)gamma(2L) GABA(A) receptors contain more than one donor for the hydrogen-bond-acceptor group of anesthetic steroids. The family of cyclosteroids should be useful for future structure-activity relationship studies of steroid modulation of other GABA(A) receptor subtypes.


Subject(s)
Anesthetics/chemical synthesis , GABA Modulators/chemical synthesis , Norsteroids/chemical synthesis , Pregnanolone/analogs & derivatives , Pregnanolone/chemical synthesis , Anesthetics/pharmacology , Animals , Behavior, Animal/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Electrophysiology , Female , GABA Modulators/pharmacology , In Vitro Techniques , Larva , Models, Molecular , Norsteroids/pharmacology , Oocytes , Patch-Clamp Techniques , Pregnanolone/pharmacology , Radioligand Assay , Rats , Receptors, GABA-A/drug effects , Receptors, GABA-A/metabolism , Receptors, GABA-A/physiology , Structure-Activity Relationship , Xenopus laevis
14.
Farmaco ; 58(9): 765-80, 2003 Sep.
Article in English | MEDLINE | ID: mdl-13679169

ABSTRACT

Three series of N-acyl and N-cyclohexyl- or N-methyl or N-phenyl-thioureas of 4-substituted (methyl, phenyl, 2-pyridyl)piperazines (4-12) were synthesised according to a highly convergent one-pot procedure and tested in vivo (local anaesthetic, anti-hyperlipoproteinemic, analgesic, anti-inflammatory, antiarrythmic activities) and in vitro (antiaggregating and, for some selected derivatives, antiproliferative activities) experiments. All the test compounds showed local anaesthesia in particular 4Ar(4), 5Ar(4), 12Ar(3) (after 5 min) and 5Ar(2), 5Ar(3), 9Ar(4) (after 30 min) were equipotent to lidocaine. In lowering triglyceride levels, compounds 6Ar(4) and 7Ar(3) were more active than nicotinic acid, whereas 7Ar(4) and 11Ar(4) were approximately equipotent. As concerns analgesic activity, 5Ar(2) and 5Ar(4) were as active as indomethacin. Appreciable anti-inflammatory activity was found in 8Ar(1), 5Ar(2) and 11Ar(2), but inferior to that of indomethacin. High levels of antiarrythmic activity, comparable with that of quinidine, were found in derivatives 4Ar(2) and 10Ar(1). Compounds 4Ar(2) and 8Ar(2), assayed in antitumor in vitro screening system at National Cancer Institute (NCI), showed significant antiproliferative activity against ACHN cell line (GI50: 0.13 microM) and NCI-H226 cell line (GI50: 1.03 microM), respectively.


Subject(s)
Analgesics/chemical synthesis , Anesthetics/chemical synthesis , Anti-Arrhythmia Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Piperazines/chemical synthesis , Platelet Aggregation Inhibitors/chemical synthesis , Thiourea/analogs & derivatives , Thiourea/chemical synthesis , Analgesics/pharmacology , Anesthetics/pharmacology , Animals , Anti-Arrhythmia Agents/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Humans , Hypolipidemic Agents/pharmacology , Piperazines/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Thiourea/pharmacology
15.
Steroids ; 68(7-8): 677-83, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12957673

ABSTRACT

Three groups of (5 alpha,13 alpha)-D-azasteroids, (5 alpha,13 alpha)-3-hydroxy-17a-aza-D-homoandrostans (12), (5 alpha,13 alpha)-3-hydroxy-17-aza-D-homoandrostans (15), and (5 alpha,13 alpha)-3-hydroxy-17-azaandrostans (17), were designed and synthesized as key precursors for the further preparation of a new family of potential GABAA receptor modulators from commercially available natural steroids (5 alpha)-3-hydroxyandrostane-17-ones (7).


Subject(s)
Azasteroids/chemical synthesis , GABA-A Receptor Agonists , GABA-A Receptor Antagonists , Anesthetics/chemical synthesis , Azasteroids/pharmacology , Drug Design , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Structure-Activity Relationship
17.
J Med Chem ; 43(22): 4118-25, 2000 Nov 02.
Article in English | MEDLINE | ID: mdl-11063608

ABSTRACT

Various cyclic ether and other 3 alpha-hydroxyandrostane derivatives bearing a conformationally constrained hydrogen-bonding moiety were prepared. Their anesthetic potency and their binding affinity for GABA(A) receptors, measured by intravenous administration to mice and inhibition of [(35)S]TBPS binding to rat whole brain membranes, were compared with that of known anesthetic 3 alpha-hydroxypregnan-20-ones. Synthetic steroids with similar in vitro and in vivo activities to the endogenous 3 alpha-hydroxypregnan-20-ones all had an ether oxygen on the beta-face of the steroid D-ring. These results suggest that for optimal GABA(A) receptor modulation, the hydrogen bond-accepting substituent should be near perpendicular to the plane of the D-ring on the beta-face of the steroid.


Subject(s)
Androstanols/chemical synthesis , Anesthetics/chemical synthesis , GABA Modulators/chemical synthesis , Receptors, GABA-A/drug effects , Androstanols/chemistry , Androstanols/pharmacology , Anesthetics/chemistry , Anesthetics/pharmacology , Animals , Brain/metabolism , GABA Modulators/chemistry , GABA Modulators/pharmacology , Hydrogen Bonding , In Vitro Techniques , Injections, Intravenous , Mice , Models, Molecular , Radioligand Assay , Rats , Receptors, GABA-A/metabolism , Structure-Activity Relationship
19.
J Med Chem ; 40(11): 1668-81, 1997 May 23.
Article in English | MEDLINE | ID: mdl-9171876

ABSTRACT

(3 alpha,5 alpha)-3-Hydroxypregnan-20-ones and (3 alpha,5 alpha)-3-hydroxypregnane-11,20-diones bearing a 2 beta-morpholinyl substituent were synthesized, and the utility of these steroids as anesthetic agents was evaluated through determination of their potency and duration of hypnotic activity in mice after intravenous administration. Alkylation of the morpholinyl substituent or chlorination at C-21 afforded the novel amino steroids (2 beta,3 alpha,5 alpha)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione (19) and (2 beta,3 alpha,5 alpha)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one (37) that were more potent and advantageously produced shorter sleep times than related compounds which were previously reported. Furthermore, salts of these and other amino steroids generally retained good aqueous solubility. In a radioligand binding assay the compounds inhibited the specific binding of [35S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes, and in an electrophysiological assay they potentiated GABAA receptor-mediated currents recorded from voltage-clamped bovine chromaffin cells. These in vitro results are consistent with the anesthetic activity of the amino steroids being related to their modulatory effects at GABAA receptors.


Subject(s)
Anesthesia , Anesthetics/chemical synthesis , Morpholines/chemical synthesis , Pregnanediones/chemical synthesis , Receptors, GABA-A/drug effects , Receptors, GABA-A/physiology , Animals , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Cattle , Cell Membrane/metabolism , Chromaffin System/physiology , Electric Conductivity , Electrophysiology , Male , Mice , Molecular Structure , Morpholines/metabolism , Morpholines/pharmacology , Pregnanediones/metabolism , Pregnanediones/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Solubility , Structure-Activity Relationship , Water
20.
J Med Chem ; 36(1): 111-8, 1993 Jan 08.
Article in English | MEDLINE | ID: mdl-8421276

ABSTRACT

The n-bromododecane-1,12-diols with bromine on carbons 2, 3, 5, and 6, respectively, were synthesized and found to be potent general anesthetics. They were also found to be potent inhibitors of firefly luciferase, a protein model for the primary target sites underlying general anesthesia. However, their effects on lipid bilayers were small, lowering the chain-melting phase transition temperature by less than 1 degree C at their EC50 concentrations for general anesthesia. A large dependence upon the position of the bromine atom was found for both n-hexadecane/water partition coefficients and inhibition constants for firefly luciferase; a much smaller positional dependence was found for induction of general anesthesia and for disrupting lipids. These results are consistent with the bulky bromine atom inhibiting the conformational flexibility of the diol hydrocarbon chain, making these bromo diols useful probes for ascertaining the shapes of apolar binding sites. In particular, our measurements suggest that these novel anesthetics produce general anesthesia by binding to long and relatively narrow apolar target sites in the central nervous system.


Subject(s)
Anesthetics/chemical synthesis , Hydrocarbons, Brominated/chemical synthesis , Anesthesia, General , Anesthetics/chemistry , Anesthetics/pharmacology , Animals , Coleoptera , Hydrocarbons, Brominated/chemistry , Hydrocarbons, Brominated/pharmacology , Isomerism , Luciferases/antagonists & inhibitors , Luciferases/isolation & purification , Rana temporaria , Structure-Activity Relationship
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