High Analgesic Activity Research Articles

Analgesic effects of spinal cord peptide factors produced during the establishment and development of generators of pathologically enhanced excitation in the rat spinal cord

In rats with a pain syndrome caused by the production of a generator of pathologically enhanced excitation, substances of peptide nature with analgesic properties were found to be produced in the nociceptive system of the spinal cord. Spinal cord extracts derived from rats with such syndromes (pain syndrome of spinal origin or adjuvant arthritis) exerted analgesic effects when injected intraventricularly into recipient rats with a pain syndrome of spinal origin. The highest analgesic activity was displayed by extracts obtained from the region where the generator of pathologically enhanced excitation had been set up. The analgesic activity of the extracts was directly related to the severity and duration of the pain syndrome in the donor rats.

Analgesic and Antiinflammatory Effects of Some New 6-Acyl-3-substituted-2(3H)-benzoxazolone Derivatives

6-Acyl-2(3f-benzoxazolone derivatives were reacted with 4- substituted phenacyl bromide in ethanol to give the corresponding 6-acyl-3- [(4-substltutedbenzoyl)methyl] -2(3W)-benzoxazolones. The compounds were screened for their analgesic, antiinflammatory activities. The eight compounds synthesized showed high analgesic activities and further investigation revealed compounds 3, 6 and 7 to be potent inhibitors of carrageenan- and arachidonic acid-induced paw edema. The PGE2 isolated from the carrageenan paw edema fluid was also significantly low in mice treated with compounds 3, 6 and 7.

Linear and cyclic β-casomorphin analogues with high analgesic activity

We investigated the antinociceptive efficacy of casomorphin (CM) derivatives using the vocalization test. Male Wistar rats received chronic microcannulae into the right lateral ventricle. One week later we examined the analgesic effect of CM derivatives 10, 30, 60, and 90 min after intraventricular injection (5 μl). The analgesic effect was calculated as the individual percent increase in the pain threshold and was compared to controls (saline treatment). The substitution of d-lysine and d-ornithine in position 2 in connection with a cyclization through ring closure of the 2 position side chain amino group to the C-terminal glycine-COOH group resulted in high analgesic potency. The substitution of d-Pro 4 was without any effect in the ineffective linear derivatives and decreased the effectiveness in the highly effective cyclic derivatives. The cyclic [ d-Orn 2]CM-5 and the cyclic [ d-Lys 2]CM-5 are the CM derivatives with the highest antinociceptive activity. The cyclic [ d-Orn 2]CM-5 is greater than 1000 times more effective than morphine. We conclude, on the basis of studies of receptor binding and in vitro investigations, that μ receptor activity alone is not responsible for the analgesic activity. The δ receptor and possibly also the κ receptor could modulate the nociceptive effectiveness.

Potentiometric, calorimetric and spectroscopic study of copper(II) complexes of leucine-enkephalin and tripeptides containing tyrosine

Complexation of Copper(II) ion with three peptides containing tyrosine residue (Gly-Gly-L-Tyr, L-Tyr-Gly-Gly and Leucine-enkephalin) was studied by pH-metric, visible spectroscopic measurements at 25°C and 0.2 mol dm-3 KNO3 , e.s.r spectra and calorimetric technics at 25 ± 0.001°C and I = 0.5 mol dm-3 KNO3 . Four species have been reported for Cu(II)-tripeptide systems, while five species have been described in the Cu(II)-Leucine-enkephalin one. The three peptides containing tyrosine display in aqueous solutions the same chelation mode as for simple peptides. Besides, the phenolic hydroxy group in the side chain does not play a direct role in co-ordination to the cupric ion. The MH-2 A species of Cu(II)-Leucine-enkephalin system is more stable when compared to the same species of Cu(II)-simple peptide (with no Tyr residue). Moreover, the value of the formation enthalpy of this species is less endothermic, and its entropy variation is more negative, than in the case of L-Tyr-Gly-Gly and Gly-Gly-L-Tyr. These favorable thermodynamic conditions and structural considerations permit to explain the reported high analgesic activity of Cu(II)-Leucine-Enkephalin complexes compared to the free Leucine-Enkephalin analgesic activity.

Synthesis and conformational analysis of a series of galactosyl enkephalin analogues showing high analgesic activity.

Two galactosyl derivatives of [DMet2,Pro5] enkephalin-amide (compound 1), namely [DMet2,Pro5] enkephalin [N1.5-beta-D-galactopyranosyl] amide (compound 2) and O1.5-(beta-D-galactopyranosyl) [DMet2,Hyp5] enkephalin-amide (compound 3) have been synthesized. Such glycosylpeptides have been shown to be extremely potent analgesic agonists. The conformational analysis of these three compounds in DMSO-d6 solution has been carried out using two-dimensional NMR methods. Both the parent compound (1) and the beta N-galactosyl derivative (2) show similar NMR parameters which are consistent with fairly rigid beta-strands at both the N-terminus and C-terminus, connected by a glycine residue that displays a mixture between multiple conformational states. Thus, although the beta N-galactosyl derivative (2) has been shown to be significantly more potent than the parent compound (1) in the tail immersion and paw pressure tests of analgesia, no correlation can be established between the conformation of (1) and (2) in DMSO and the difference in analgesic activity. In contrast, important conformational differences with respect to (1) and (2) have been detected in the beta O-galactosyl derivative (3). In this case, only one of the likely conformations for (1) and (2) are consistent with the experimental data. These data show that the position of the galactose residue in compound (3) causes Gly3 to loose flexibility leading to a more rigid folded conformation. Such a change in conformation could be related to the difference in analgesic activity between (2) and (3).

Studies on analgesic oligopeptides. V. Structure--activity relationship of tripeptide alkylamides, Tyr-D-Arg-Phe-X.

Twenty-one analogs based on the structure Tyr-D-Arg-Phe-X (X=OH, alkyl ester, alkylamide or amino acid having a different carbon chain) were synthesized by the solution method and their analgesic activities were tested after subcutaneous (s. c.) administration in mice. Most tripeptide alkylamides showed no analgesia at a dose of 10 mg/kg, s. c. However, some tripeptide alkylamides having the hydroxyl group on the alkyl moiety showed greater activity than morphine. Introduction of the carboxyl group on the alkyl moiety also led to tetrapeptide analogs with potent analgesia, e. g., the compound with X=β-alanine is 33 times more potent than morphine on a molar basis. These results suggest that proper carbon chain lengths and the presence of an oxygen atom at the fourth position are important for high analgesic activity in the series of D-Arg2-dermorphin analogs.

Studies on peptides. CXXXI. Synthesis of adrenorphin and enkephalin analogs.

Adrenorphin, H-Tyr-Gly-Gly-Phe-Met-Arg-Arg-Val-NH2, and its D-Met (O)2-analog were synthesized. In addition, analogs of [Arg6, Phe7] enkephalin substituted at the 2nd position by D-Ala and D-Met (O) were also synthesized, together with four other enkephalin analogs. Among these compounds, [D-Met (O)2] adrenorphin exhibited high analgesic activity (29.1 times that of morphine) antagonized by naloxone, when administered intracisternally to mice.

ChemInform Abstract: Morphinans and 6‐Ketomorphinans Unsubstituted in the Aromatic Ring. High Analgesic Activity of (‐)‐6‐Keto‐N‐methylmorphinan. Part 4.

AbstractDie Eliminierung der OH‐Funktion im (J‐A1‐Hydroxy‐ö‐keto‐N‐methylmorphinan (Ia) durch Hydrierung des Ethers (Ib) führt zum Ketomorphinan (IIa), aus dem die Derivate (IIb)‐(IId) sowie durch Reduktion das Morphinan (III) hergestellt werden.

Further synthesis of enkephalinol analogs containing the dipeptide unit Tyr-Arg (kyotorphin).

In order to obtain enkephalin derivatives with high analgesic activity, four enkephalinol analogs having the Tyr-D-Arg unit in the N-terminal position were synthesized. Of these, H-Tyr-D-Arg-Gly-MePhe-Met (O)-ol exhibited analgesic activity comparable to that of morphine after intravenous administration to mice.

ChemInform Abstract: BICYCLIC ANALOGS OF PIPERAZINE. XIII. DERIVATIVES OF 3,8‐DIAZABICYCLO(3.2.1)OCTANES WITH POTENTIAL ANTIINFLAMMATORY ACTIVITY

AbstractN‐Methyl‐diazabicyclooctane (I) wurden mit Säurechloriden bzw. Chloressigsäureestern zu Amiden bzw. Dialkyldiazabicyclo‐octanen (II) und (III) umgesetzt.