Opioid and non-opioid effects of novel butyrophenone analogues.

Haloperidol, haloperidol propionate, and a haloperidol analogue N-3-(p-fluorobenzoyl) propyl-4-phenyl-4-propionyl-oxypiperidine (NIH 10495) were evaluated in several in vitro and in vivo tests of opioid effects. Haloperidol bound to opioid receptors with very low affinity and had no opioid agonist effects in the other test systems. Haloperidol propionate was 10 times less potent than NIH 10495 in the binding assay and in the smooth-muscle assay. Both of these haloperidol analogues decreased the rate and volume of respiration in air and in 5% CO2 with NIH 10495 being approximately 50 times more potent than haloperidol propionate. The NIH 10495, but not the haloperidol propionate, attenuated naltrexone-like discriminative stimulus effects in morphine-dependent withdrawn rhesus monkeys. Intravenously delivered NIH 10495 maintained higher rates of responding than did haloperidol propionate when evaluated for reinforcing effects. These drugs appear to have novel spectra of action that suggest possible value for this synthetic approach to the development of clinically useful analgesics and to the development of novel neuroleptics.

Synthesis, stereochemistry, and biological activity of the 1-(1-phenyl-2-methylcyclohexyl)piperidines and the 1-(1-phenyl-4-methylcyclohexyl)piperidines. Absolute configuration of the potent trans-(-)-1-(1-phenyl-2-methylcyclohexyl)piperidine.

The (-)- and (+)-isomers of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines have been synthesized and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines were prepared, and their in vitro [displacement of [3H]TCP (1-[1-(2-thienylcyclohexyl)]piperidine) from the PCP (1-(1-phenylcyclohexyl)piperidine) binding site] and in vivo (rotarod assay) activities determined. The 1-(1-phenyl-2-methylcyclohexyl)piperidine isomers were resolved by classical crystallization procedures, through the diastereomeric salts obtained with d- and l-10-camphorsulfonic acid. The relative stereochemistry of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines was established by using 13C and 1H NMR. Both (-)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((-)-2) and (+)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((+)-2) were examined by single-crystal X-ray analysis, and the absolute configuration of (-)-2 was determined to be 1S,2R. The (-)-2 was found to be about five times more potent than PCP in vitro and twice as potent in vivo. It is the most potent of all of the simple methyl-substituted cyclohexyl PCP isomers and is among the most potent PCP-like compounds which have been synthesized. It was nine times more potent in vitro and four times more potent in vivo than (+)-2. The racemic cis-1-(1-phenyl-2-methylcyclohexyl)piperidine (3), and its enantiomers ((+)-3 and (-)-3), were essentially inactive in vitro and in vivo. The cis-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (18) was more potent than trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (17), but considerably less potent than (-)-2. The enantioselectivity observed at the PCP binding site for (-)-2 could indicate that this site can discriminate between enantiotopic edges of the achiral PCP (choosing the pro-1-S edge), as does the mu-opioid receptor in the prodine series of opioids. Benzimidoyl or benzoyl group replacement of the phenyl ring in the 1-(1-phenyl-2-methylcyclohexyl)piperidine series gave compounds which showed little in vitro and in vivo activity.

Common stereospecificity of opioid and dopamine systems for N-butyrophenone prodine-like compounds.

The two optical isomers of 1-[3-(p-fluorobenzoyl) propyl]-3-methyl-4-phenyl-4-propionoxypiperidine (FPP) were obtained by resolution of (+/-)-r-3-methyl-4-phenyl-c-4-piperidinol followed by N-alkylation and O-propionylation. These, as well as the racemate, were evaluated for their antinociceptive, opioid, and neuroleptic properties using in vivo and in vitro test systems. The results are remarkable in two respects, namely, the dextrorotatory isomer is consistently the most potent on all tests, and it acts on both opioid (mu) and neuroleptic (D2) receptors.

In vivo effect of eflornithine (DFMO) and some related compounds on Leishmania infantum preliminary communication.

An in vivo method was used to test the effect of eflornithine (DFMO) and five related compounds on Leishmania infantum amastigotes. Treatment with 100 mg/kg sc for 5 days of Leishmania infected Balb/c mice yielded a parasite inhibition ranging from 56% (compound 2, "reverse arginine") to 85% (eflornithine), these values being lower than that obtained with the reference compound Glucantime (93%). In long-term treatment (40 days) the two selected compounds, eflornithine and 3 ("reverse homoarginine"), failed to cure the animals. However, in dose response experiments these drugs showed to be effective at very low doses when compared with Glucantime, thus suggesting that they might be of potential value in the chemotherapy of leishmaniases.

Combined analgesic/neuroleptic activity in N-butyrophenone prodine-like compounds.

Some 4-phenyl-4-piperidinols, corresponding esters, and related compounds with a p-fluorobutyrophenone chain on nitrogen were synthesized and evaluated in in vitro and in vivo tests in order to examine their ability to interact contemporaneously with opioid and dopamine receptors. The propionyloxy derivatives showed a good combination of analgesic and neuroleptic activity. With a 3-methyl substituent on the piperidine ring, the beta-configuration was the more active form not only for analgesic activity, as expected from previous results on prodines, but also for neuroleptic activity. Haloperidol and its propionate were also tested as reference compounds.

Quantitative analysis of beta-adrenergic blocking agents by NMR spectroscopy.

The quantitative analysis by (1)H NMR of labetalol, oxprenolol and four other beta-adrenergic blocking agents is described. The method depends on the integration of selected resonances of the analyte and an internal reference which do not overlap. Procedures for the extraction of the analyte from tablets are given and corrections due to the NMR features of excipients outlined in some cases. The NMR method is reasonably precise and rapid, and the assay results compare favourably with those obtained by a UV procedure.

Syn/anti isomerization of cefuroxime by ultraviolet light.

Cefuroxime, like all the oximino cephalosporins on the market, has the methoxyimino group in the syn (Z) configuration. By U.V. light irradiation of cefuroxime, a syn/anti isomerization occurs until equilibration of the two isomers is reached. Measurement of the 1H-N.M.R. chemical shift differences of the two isomers allows the assignment of methoxyimine stereochemistry.

Chemistry and in vitro mutagenicity of 2-aminofluorene derivatives.

A study on the relationship between mutagenic activity and chemical reactivity of a series of 2-fluorenylamino and hydroxylamino derivatives has been carried out by assaying their ability to revert the Salmonella typhimurium strain TA98. The mutagenic potency of the fluorenamides increased with increasing availability of the amidic hydrogen for abstraction and tertiary amides were quite inactive. N-Hydroxy and N-acyloxy derivatives were directly mutagenic and increased their mutagenic activity after metabolic conversion by liver S9. N-Hydroxy-2-benzoylaminofluorene, inactive without S9, after activation was the most mutagenic. Of a pair of N-acyloxy-derivatives, N-benzoyloxy-2-acetylaminofluorene, which undergoes rearrangement of the benzoyloxy group from nitrogen to ring carbons even at room temperature, was less potent than N-acetyloxy-2-acetylamino-fluorene whose rearrangement occurs at higher temperatures. Corresponding C-1 and C-3 benzoyloxy and acetyloxy derivatives were found ineffective in this assay in agreement with previous reports on the hydroxy series. N-Chloro-2-amino-(or acetylamino)fluorene were found more active than the corresponding N-hydroxy analogs in the presence of S9, thus suggesting an alternate pathway for activation, likely a direct conversion to electrophilic species. Furthermore, in contrast with inactivity of ring hydroxy and acyloxy derivatives, 3-chloro-2-acetylaminofluorene retained mutagenic activity. Finally 2,2'-azoxyfluorene, the ultimated oxidation product of N-hydroxyaminofluorene, tested in vitro and in vivo experiments, was found completely inactive.

Nitrogen analogues of phencyclidine: 1-alkyl-4-phenyl-4-(1-piperidinyl)piperidines.

In order to investigate the effect of the introduction of a nitrogen atom in the alicyclic moiety of phencyclidine (PCP) a series of 1-alkyl-4-phenyl-4-(1-piperidinyl)piperidines were synthesized. The in vivo assays in mice and EEG in rabbits indicated that the presence of a second basic center in the molecule resulted in a loss of PCP-like activity. The new compounds were devoid of analgesic activity.

Biological effects of modified colchicines. 2. Evaluation of catecholic colchicines, colchifolines, colchicide, and novel N-acyl- and N-aroyldeacetylcolchicines.

A series of natural and synthetic colchicine derivatives was examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein. The natural alkaloids cornigerine and colchifoline and several N,O-substituted analogues of colchifoline were found to be as potent and as toxic as colchicine in the P388 screen with good affinity for tubulin. The 1,2-(methylenedioxy)-substituted isomer of cornigerine was considerably less potent in vivo than could have been anticipated from the in vitro tubulin binding data. Several N-acyl and N-aroyl derivatives prepared from deacetylcolchicine showed high potency in the in vitro and in vivo screens. Colchicide was found to be highly potent in vivo, and N-carbethoxydeacetylcolchicine, a synthetic analogue of colchicine with a N-carbethoxy instead of an N-acetyl function, showed interesting biological properties.

Biological effects of modified colchicines. Improved preparation of 2-demethylcolchicine, 3-demethylcolchicine, and (+)-colchicine and reassignment of the position of the double bond in dehydro-7-deacetamidocolchicines.

A variety of colchicine, demecolcine, and isocolchicine derivatives were examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein. A qualitatively direct correlation was found between in vivo potency and toxicity; potency appeared to be less well correlated with tubulin binding. The most potent compounds were N-acylated analogues of colchicine and demecolcine. Among the monophenols, only 3-demethylcolchicine showed an appreciable effect in vitro and in vivo and was less toxic than colchicine. Improved methods were found for the preparation of 3- and 2-demethylcolchicine, which involved the use of 85% phosphoric acid and concentrated sulfuric acid, respectively. Decoupling experiments with 1H NMR proved that the double bond of dehydro-7-deacetamidocolchiceine and its derived tropolonic methyl ethers 24 and 25 was in the 5,6 position, rather than the 6,7 position formerly tentatively assigned.

Nalorphine-like properties of some 2,3-dimethyl-3-arylpiperidines.

A number of N-substituted 2,3-dimethyl-3-arylpiperidines having an m- or p-arylhydroxyl were prepared and evaluated for analgesic agonist and antagonist properties. The diastereomeric N-allyl and N-cyclopropylmethyl derivatives behaved as pure potent antagoinists. Substitution of the arylhydroxyl from the meta to the para position resulted in a net fall of the antagoinist activity.

[Isochroman-4-spiro-4'-piperidine: synthesis and analgesic properties]. / Isocroman-4-spiro-4'-piperidine: sintesi e proprietà analgesiche

The synthesis of some isochroman-4-spiro-4'-piperidines by intramolecular O-methylation of 4-aryl-4-hydroxymethylpiperidines with formaldehyde and their analgesic activity ("hot plate"test in mice) are reported. The introduction of the new ring led to compounds with weak analgesic activity.

Relationships between opiate receptor binding and analgetic properties of prodine-type compounds.

The receptor binding affinities of some diastereoisomeric prodine analgoues have been compared with their analgetic activities determined by the hot-plate test in mice. The close correlation found between these potencies indicates that the relative analgetic activities of the alpha/beta isomers are determined primarily by the appropriate association to the receptor sites.