Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters.

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.

Ross C. Terrell, PhD, an anesthetic pioneer.

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.

Neurosteroid analogues. 14. Alternative ring system scaffolds: GABA modulatory and anesthetic actions of cyclopenta[b]phenanthrenes and cyclopenta[b]anthracenes.

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).

Liquor made quicker: alcohol as a synthetic reagent for molecules in anesthesia.

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.

Neurosteroid analogues. 10. The effect of methyl group substitution at the C-6 and C-7 positions on the GABA modulatory and anesthetic actions of (3alpha,5alpha)- and (3alpha,5beta)-3-hydroxypregnan-20-one.

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.

Synthesis, biological evaluation, and preliminary structure-activity considerations of a series of alkylphenols as intravenous anesthetic agents.

Following our discovery of the intravenous (iv) anesthetic activity of 2,6-diethylphenol in mice, a series of alkylphenols was examined in this species and the most active analogues were further evaluated in rabbits. The synthesis of compounds which were not commercially available was accomplished by adaptations of standard ortho-alkylation procedures for phenols. Structure-activity relationships were found to be complex, but, in general, potency and kinetics appeared to be a function of both the lipophilic character and the degree of steric hindrance exerted by ortho substituents. The most interesting compounds were found in the 2,6-dialkyl series, and the greatest potency was associated with 2,6-di-sec-alkyl substitution. In particular, 2,6-diisopropylphenol (ICI 35 868) emerged as a candidate for further development and has subsequently been shown to be an effective iv anesthetic agent in man.

Anesthetic steroid mobility in model membrane preparations as examined by high-resolution 1H and 2H NMR spectroscopy.

A series of structurally related pregnane analogues which exhibit a wide range of anesthetic potencies were incorporated into unilamellar egg lecithin vesicles and their relative mobilities examined with 1H and 2H high-resolution NMR spectroscopy. The data from this study reveal a trend suggesting a relationship between the motional properties of a steroid and its anesthetic potency. The data are congruent with the idea that anesthetic activity is associated with perturbation of the membrane bilayer by the steroid molecule; the degree to which the membrane is perturbed is apparently dependent upon the specific structural and stereochemical features of the steroid. This study supports the hypothesis that lipid bilayers are capable of a high degree of structural discrimination.

Synthesis and pharmacological activity of thiohexital enantiomers.

(S)-(+)- and (R)-(-)-5-Allyl-5-(1-methyl-2-pentynyl)-2-thiobarbituric acid (1, thiohexital) were prepared. The anesthetic activity (loss of righting reflex) and acute toxicity of the optically pure enantiomers of 1 were compared to the racemic isomer in mice. The S(+) isomer was found to be more potent as an anesthetic agent than the R(-) or RS(+/-) isomers. The therapeutic index was 2.5, 2.4, and 3.2 for the RS(+/-), R(-), and S(+) isomers, respectively. There were no significant differences in onset and duration of anesthesia when administered at the respective AD50 values. The prominent side effect is tremor, which is less for the S(+) isomer than for the R(-) or RS(+/-) isomers.

Synthesis and use of the n-bromododecane-1,12-diols as conformational probes for general anesthetic target sites.

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.

4-Phenyl- and 4-heteroaryl-4-anilidopiperidines. A novel class of analgesic and anesthetic agents.

The incorporation of the 4-phenylpiperidine pharmacophore found in morphine into 4-anilidopiperidines related to fentanyl (1) led to a novel class of potent opioid analgesic and anesthetic agents with a favorable pharmacological profile. The synthesis, analgesic activity, and anesthetic properties of a series of 4-phenyl-4-anilidopiperidines (13-29) are discussed. Isosteric replacement of the phenyl by various heteroaryl substituents extended the series to include 4-heteroaryl-4-anilidopiperidines (30-53). Within this group, 1-[2-(1H-pyrazol-1-yl)ethyl]-4-(4-methylthiazol-2-yl)-4-(N- phenylpropionamido)piperidine (48), exhibited high analgesic potency, short duration of action, rapid recovery of motor coordination following anesthetic doses, and greater cardiovascular and respiratory safety during anesthesia as compared with opioids fentanyl (1) and alfentanil (2) currently in clinical use. Such analgesics could be of great utility to clinicians in the expanding outpatient surgical arena and for patient-controlled analgesia and computer assisted continuous infusion pain control techniques.

Conformationally constrained anesthetic steroids that modulate GABA(A) receptors.

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.

Anesthetic activity of novel water-soluble 2 beta-morpholinyl steroids and their modulatory effects at GABAA receptors.

(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.

Neurosteroid analogues. 9. Conformationally constrained pregnanes: structure-activity studies of 13,24-cyclo-18,21-dinorcholane analogues of the GABA modulatory and anesthetic steroids (3alpha,5alpha)- and (3alpha,5beta)-3-hydroxypregnan-20-one.

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.

Preparation of (5 alpha,13 alpha)-D-azasteroids as key precursors of a new family of potential GABAA receptor modulators.

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).

Synthesis of a [1,2-3H]-labeled pregnanolone.

A method is described for the synthesis and purification of 3 alpha-hydroxy-5 alpha-[1,2-3H]pregnan-20-one. [1,2-3H]progesterone (55 Ci/mmol) was incubated with a homogenate of rat brain tissue. The product was purified by Sephadex chromatography and thin-layer chromatography. The identity and purity of the product were established by successive recrystallizations and high-performance liquid chromatography. A 34% portion of the starting material was converted to 3 alpha-hydroxy-5 alpha-[1,2-3H]pregnan-20-one. The final radiopurity of 3 alpha-hydroxy-5 alpha-pregnan-20-one obtained from four independent preparations was 94% to 99%.

3,5-Diphenyl-1H-pyrazole derivatives. VIII. N-substituted 3-(4-hydroxy-3,5-diphenyl-1H-pyrazol-1-yl)-propanamides, -propanamines and 2-(4-hydroxy-3,5-diphenyl-1H-pyrazol-1-yl)ethanamines with platelet antiaggregating, hypotensive, antiarrhythmic and other activities.

The synthesis of N,N-disubstituted 3-(4-hydroxy-3,5-diphenyl-1H-pyrazol-1-yl)-propanamides and -propanamines, starting from 4-benzoyloxy-3,5-diphenyl-1H-pyrazole, and of N-substituted 2-(4-hydroxy-3,5-diphenyl-1H-pyrazol-1-yl)ethanamines, starting from 4-acetoxy-1-(2-hydroxyethyl)-3,5-diphenyl-1H-pyrazole, is described. Some of the above compounds showed a platelet antiaggregating activity in vitro superior or comparable to that of acetylsalicylic acid, as well as moderate hypotensive, antiarrhythmic, local anesthetic, sedative and antiinflammatory activities in rats and mice.

Synthesis of N-substituted-N-acylthioureas of 4-substituted piperazines endowed with local anaesthetic, antihyperlipidemic, antiproliferative activities and antiarrythmic, analgesic, antiaggregating actions.

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.

Pharmacological evaluation of new alkylesters of 4-[(2-hydroxy-3-alkylamino)propoxy]phenylcarbamic acids with beta-adrenolytic properties.

The basic relationship between the chemical structure and pharmacological activities of new alkylesters of 4-[(2-hydroxy-3-alkylamino)propoxy]phenylcarbamic acids were evaluated. The efficiency of compounds was compared with those of metipranolol and practolol, respectively. The majority of 4-substituted derivatives of aryloxypropanolamines have shown antiisoprenaline (beta-adrenolytic) and local anesthetic (membrane stabilizing) activities. The values of LD50 and/or partition coefficients have not differed significantly when compared with those of standard metipranolol.

[1, 2, 4]-oxadiazoles: synthesis and biological applications.

In the present article synthesis and medicinal applications of [1, 2, 4] oxadiazoles are reviewed. The oxadiazoles have a wide range of applications such as Antitussive, Anti-inflammatory, Anaesthetic, Vasodilator, anthelmintic, antiallergic, antiplatelet effects in vitro, antithrombotic properties in vivo, etc. Many researchers have synthesized novel heterocyclic compounds containing oxadiazoles with the concept of bioisosterism.