Nicafenine, a new analgesic. I. Synthesis and physicochemical properties.

The synthesis of 2-[(7-chloro-4-quinolyl)-amino] benzoic acid 3-pyridine carboxamide-N-ethyl ester (nicafenine) was carried out by a new method using isatoic anhydride. The IR, NMR, MS and UV spectrophotometric studies are described, together with the characteristics of this compound.     

Some 9-hydroxycannabinoid-like compounds. Synthesis and evaluation of analgesic and behavioral properties.

A series of 9-hydroxylated cannabinoid-like compounds was prepared and tested for analgesic properties in mice and behavioral properties in dogs. Although the prototype compound, 9-nor-9-hydroxyhexahydrocannabinol, has potent antinociceptive activity in laboratory animals, the new analogues were relatively inactive. All of the compounds produced an alteration of behavior in unanesthetized dogs. Two of the compounds produced cannabinoid-like effects and the other two produced general CNS depression.     

Synthesis and analgesic and antiinflammatory properties of new benzodiazepine derivatives

Several new N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides have been synthesized and characterized with respect to acute toxicity (LD₅₀), analgesic and antiinflammatory properties (formalin-and carrageenan-induced foot edema models), and interaction with morphine-induced antinociception in mice. The new compounds were prepared by acyl coupling of 2-aminobenzophenones with α-(benzotriazol-1-yl)-N-acylglycines followed by displacement of the benzotriazole ring with ammonia and cyclization of the resulting monoacyl aminals. The LD₅₀ of the synthesized compounds exceeds 1000 mg/kg. Three compounds produced significant analgesic action in doses 100–150 μg/kg in the early (painful) phase of the formalin test and potentiated the morphine-induced antinociception in this test. The synthesized drugs neither showed antinociception in the second (inflammatory) phase of the formalin test nor decreased the carrageenan-induced foot edema growth. Thus, the synthesized compounds produce analgesic action but do not possess antiinflammatory properties. The analgesic activity is probably due to the interaction with μ-and δ-opioid receptors. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 12, pp. 21–23, December, 2005.     

Synthesis of some 2-benzoxazolinone derivatives and their analgesic properties

In this study, eight new 1-(2-benzoxazolinone-6-yl)-2-(4-arylpiperazine-1-yl)ethanol and -propanol derivatives have been prepared. Their structures have been elucidated by IR- and 1H-NMR-spectra and by elementary analysis. The analgesic activities of these compounds, using modified Koster's test have been investigated. 1-(5-Chloro-3-methyl-2-benzoxazolone-6-yl)-2-[4-(2-methoxyphenyl)p iperazine-1- yl]ethanol has been found more active than O-acetyl-salicylic acid, respectively.     

Synthesis and analgesic properties of N-phosphorylated derivatives of Phe-Ala and Phe-Gly

N-Phosphoryl dipeptides derived from Phe-Ala, Phe-Ala-NH₂ and Phe-Gly-NH₂ were synthesized and their analgesic activity was evaluated in mice. Intracere-broventricular administration of P-Phe-Ala-NH₂ produced a 100-fold increase in the analgesic potency of Phe-Ala and led to a potentiation and prolongation of the analgesic effect of the exogenously administered Met-enkephalin.     

Synthesis and analgesic activity of some 1-benzyl-2-substituted-4,5-diphenyl-1H-imidazole derivatives.

In this study, derivatives of 1-benzyl-2-substituted-4,5-diphenyl-1H-imidazole were synthesized and their analgesic activity assayed in two tests. 1,2,4,5-Tetrasubstituted imidazole compounds were obtained by the treatment of purified imidazole compounds with benzyl chloride in the presence of sodium hydride. The structure elucidation of the compounds was performed by IR, 1H-NMR and mass spectroscopic data and elemental analysis results. Generally the prepared compound exhibited only moderate analgesic activity in mice at the dose of 100 mg/kg i.p.; however, a few of them exhibited good activity, almost equivalent to that of morphine at 1 mg/kg i.p. was observed. At the above dosage, no toxicity was observed for all compounds.     

Synthesis and analgesic properties of new 4-arylhydrazone 1-H pyrazole [3,4-b] pyridine derivatives

Based on the principle of bioisosterism, a successful strategy in the planning of new drugs, we describe in this work the synthesis and the analgesic activity of the new functionalized arylcarbaldehyde 4-(1-phenyl-3-methylpyrazolo[3,4-b]pyridine) hydrazone derivatives 5a-m. These derivatives (5a-m) were synthesized in ca. 45% overall yield, using 4-(1-phenyl-3-methylpyrazolo[3,4-b]pyridinyl) hydrazine 6, as key intermediate, by applying classical synthetic methods to construct the aryl-hydrazone unit at C-4 of the heterocyclic system. Compound 6 was prepared from the corresponding 4-chloro-(N-phenyl-3-methylpyrazolo[3,4-b]pyridine) derivative 7 in very high yield. The antinociceptive activity of these new compounds 5a-m was evaluated by a test of abdominal contortions induced by 0.6% acetic acid solution i.p. in albino mice. The compounds 5f, 5g, 5j and 5k were strongly active showing a good analgesic profile.     

Synthesis and analgesic activity of some triazoles and triazolothiadiazines.

The synthesis of some triazoles and triazolothiadiazines starting from (5,6,7,8-tetrahydronaphthalen-2-yl)oxyacetic acid is described. The chemical structure of the compounds were elucidated by analytical, IR, 1H NMR and mass spectral studies. Some of the newly synthesized compounds were tested for analgesic activity and compounds 5b, 5c, and 5d exhibited promising analgesic activity.     

Discriminative stimulus properties of narcotic analgesic drugs.

This paper presents a comprehensive review on the experimental data relevant to the discriminative stimulus properties of narcotic analgesic drugs. The narcotic cue is defined as the discriminative stimulus complex which is exclusively associated with the specific central action(s) of narcotic analgesic drugs. The first part of this review discusses evidence that narcotics can act as a discriminative stimulus, and that this cue is an exclusive, complexly composed, and centrally originating property of narcotics. The pharmacological and biochemical specificity of the narcotic cue is supported by findings indicating (1) that chemically heterogenous narcotics generalize with narcotic agonist training drugs, (2) a close correlation between narcotic cuing and analgesic potency of narcotics, (3) that the requirement of steric specificity applies, and (4) the naloxone-reversibility of this cue. The comparative data so far available are thus consistent with the assumption that the narcotic cue in laboratory animals relates intimately to, and can serve as a preclinical model for opiate-like subjective effects in man. Further discussion is concerned with the involvement of various neurotransmitter substances in the narcotic cue; much as it appears likely that multiple and diffusely organized brain sites rather than discrete brain areas are involved, there is no evidence at this stage that any single transmitter would play a unique role in this cue. The other issues being discussed here are (1) the role of training drug dose, (2) the tolerance problem, (3) the relation between the narcotic cuing and the analgesic activity of narcotics, (4) the involvement of neuropeptides, (5) drug cue conditioning to environmental stimuli; (6) drug cues and drug states, and (7) the internal discriminative stimulus control of behavior by endogenous opioid substances.     

Synthesis of 4(1H)-pyridinone derivatives and investigation of analgesic and antiinflammatory activities.

This paper describes recent results of a research program aimed at the synthesis and pharmacological evaluation of new 4(1H)-pyridinone derivatives belonging to the 1,3-disubstituted series (4-11). These compounds were structurally planned by applying the molecular hybridization strategy on previously described 1,2-disubstituted-4(1H)-pyridinone derivatives, considered as lead compounds, which present potent analgesic properties (M.D. Aytemir, T. Uzbay, D.D. Erol, Arzneim. Forsch. (Drug Res.) 49 (1999) 250). Their chemical structures have been proved by means of their IR and 1H NMR data and by elemental analysis. The analgesic profile of the title compounds (4-11), evaluated by the model of abdominal constrictions induced by acetic acid, showed that all the 4(1H)-pyridinone derivatives were active, exhibiting an analgesic activity comparable with that of aspirin (acetyl salicylic acid) used as a standard. The antiinflammatory profile of the synthesized compounds, evaluated by the model of carrageenan rat paw edema, showed that all compounds were active and were comparable with indomethacin used as a standard.