Synthesis and analgesic effects of novel β2-tryptophan hexapeptide analogs.

Aiming to develop more potent analgesic substances a new series of hexapeptides containing β(2)-tryptophan analogues was synthesized. The Trp in position 4 and 5, respectively in Ac-Arg-Phe-Met-Trp-Met-Lys-NH2 (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 (highly potent and selective NOP-receptor agonist) was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or the (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The analgesic effect of the four newly synthesized compounds has been evaluated in male Wistar rats by PP- and HP tests and compared to the native templates.

Synthesis of an MIF-1 analogue containing enantiopure (S)-α-trifluoromethyl-proline and biological evaluation on nociception.

The synthesis and the effect of a novel MIF-1 analogue on nociception during acute pain in rat model are reported. The synthesis of this enantiopure trifluoromethyl group containing tripeptide was performed through a peptide coupling reaction between the HCl. Leu-Gly-NH2 and the (S)-α-Tfm-proline.

Effects of D-kyotorphin on nociception and NADPH-d neurons in rat's periaqueductal gray after immobilization stress.

D-kyotorphin (D-Kyo) is a synthetic analogue of the neuropeptide kyotorphin and produces naloxone reversible analgesia. Stress-induced analgesia (SIA) is an in-built mammalian pain-suppression response that occurs during or following exposure to a stressful stimulus. The periaqueductal gray (PAG) is implicated as a critical site for processing strategies for coping with different types of stress and pain and NO affects its activity.

Effect of Tyr-MIF-1 peptides on blood ACTH and corticosterone concentration induced by three experimental models of stress.

1. Studies, using a wide variety of stressors, have clearly indicated that the pattern of neuroendocrine response is dependent upon the stress stimulus applied. 2.

Study on the antinociceptive action of Tyr-K-MIF-1, a peptide from the MIF family.

1. Tyr-K-MIF-1 is a melanocyte inhibiting factor (MIF) neuropeptide, isolated from the brain. Opposite to other MIFs (Tyr-MIF-1, Tyr-W-MIF-1), it has a very low affinity for opiate mu-receptors, but interacts with Tyr-MIF-1 specific binding sites.

Ligand-based design, synthesis and primary in vivo screening of pyrrole derivatives as potential tricyclic anti-inflammatory agents.

Twelve new compounds were designed as 5-aryl-1H-pyrrole analogs of celecoxib (CAS 169590-42-5) and were synthesized by Paal-Knorr cyclization in three series according to 1H-substitution: derivatives with salicylic acid, pyrazolone or isonicotinamide residues. The average physico-chemical and steric similarity between the prototype and the new analogs (completed with two previously synthesized related products) was assessed to be 82 % and therefore considered as a reliable prerequisite for spatial compatibility and effective binding to the cyclooxygenase (COX) enzymes. The anti-inflammatory effects were determined in acute inflammation model using the carrageenan-induced rat paw edema assay on male Wistar rats (180-200 g) at doses of 10, 20 and 40 mg/kg, i.

Further evaluation of a series of anti-inflammatory N-pyrrolylcarboxylic acids: effects on the nociception in rats.

The analgesic activity of nine substituted N-pyrrolylcarboxylic acids, previously reported as anti-inflammatory agents, has been evaluated. The effects on nociception were examined in male Wistar rats by the Randall-Selitto paw-pressure test. The compounds were administrated in doses 10, 20, and 40 mg/kg both i.

Involvement of H2-receptors in the mechanism of analgesic action of Tyr-MIF-1.

The antinociceptive effects of H2-agents cimetidine (CIM) and dimaprit (DMP) as well as their effects on the Tyr-MIF-1-evoked analgesia have been studied after intraperitoneal (i.p.) administration in rats.

3D-QSAR and preliminary evaluation of anti-inflammatory activity of series of N-pyrrolylcarboxylic acids.

The present study focuses on development of new potential inhibitors of cyclooxygenase-2 (COX-2): series of N-pyrrolylcarboxylic acids. 3D-QSAR (Quantitative Structure-Activity Relationship) CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Index Analysis) models for predicting inhibitory activities against COX-1 and COX-2 as well as for evaluating in vivo anti-inflammatory activity were obtained and used for preliminary screening of new anti-inflammatory N-pyrrolylcarboxylic acids. Nine compounds were selected for in vivo testing and evaluated for their potency to decrease carrageenin-induced edema in rats.

Antiopioid properties of the TYR-MIF-1 family.

The Tyr-MIF-1 family of peptides includes MIF-1, Tyr-MIF-1, Tyr-W-MIF-1 and Tyr-K-MIF-1, which have been isolated from bovine hypothalamus and human brain cortex. All these peptides interact with opioid receptors and in addition bind to non-opiate sites specific for each of the peptides. Data in the literature suggest that peptides of the Tyr-MIF-1 family (Tyr-MIF-1s) have antiopioid and opioid- like effects.

Effects of Tyr-MIF's family of peptides on immobilization stress-induced antinociception in rats.

Unlabelled: The Tyr-MIF-1 family of peptides includes MIF-1, Tyr-MIF-1, Tyr-W-MIF-1 and Tyr-K-MIF-1, which have been isolated from bovine hypothalamus and cortex of human brain. Data in the literature suggest that peptides of Tyr-MIF-1's family have opioid-like and anti-opioid actions. All these peptides interact with opioid receptors and in addition bind to non-opiate sites specific for each of the peptides and able to inhibit the expression of some forms of stress-induced analgesia (SIA) in various species.

Effects of kyotorphin and analogues on nociception and pentylenetetrazole seizures.

Unlabelled: Kyotorphin (Kyo) is synthesized in specific brain regions where it may modulate synaptic transmission and directly excites cortical neurons, and indirectly exerts opioid actions to produce analgesia via release of met-enkephalin. Kyo is formed by specific enzyme from L-tyrosine and L-arginine in the presence of ATP and Mg2+ in the brain. Kyo and its analogues Tyr-Cav, Tyr (Cl2)-Cav exerted naloxone-reversible antinociception by paw-pressure test.

Effect of D-arginine on antinociception induced by kyotorphin, Tyr-cav, L-cav and Tyr(Cl2)-cav in rats.

Kyotorphin (Kyo) is synthesized in specific brain regions where it may modulate synaptic transmission. Kyo directly excites cortical neurons, and indirectly exerts opioid actions to produce analgesia via the release of [Met]-enkephalin. Kyo is formed by a specific enzyme from L-tyrosine, L-arginine (L-arg) and ATP in the presence of Mg2+.

Antiinflammatory and analgesic effects of Carthamus lanatus aerial parts.

Fractions of methanol, dichloromethane, water extracts and volatiles of Carthamus lanatus aerial parts given by oral route at a dose of 2 mg/kg showed significant antiinflammatory activities in rats. On the contrary, only the water fraction of MeOH extract possesses a significant analgesic activity.

Involvement of nitric oxide in the nociception of kyotorphin, TYR-CAV and MIF-s analogues in the rat spinal cord.

The spinal analgesic effects of Kyotorphin (Kyo) and Melanocyte-inhibiting factor (MIF-l) were studied during acute pain in rats chronically implanted with intrathecal (i.t.) cannulas.

Effects of newly synthesized analogs of MIF-1 containing unnatural amino acids on electrically evoked smooth muscle contractions.

New MIF-1 (Pro-Leu-Gly-NH2) analogs containing unnatural amino acids such as L-canavanine (Cav) and L-cysteic acid S-(2-aminoethyl)amide (sLys) have been synthesized and in vitro experiments were performed to study their action on neurotransmission in target tissues with adrenergic and cholinergic neurotransmission. The experiments were carried out on electrically stimulated proximal guinea pig ileum (GPI) and the prostatic part of rat and rabbit vasa deferentia (VDR, VDRabb). The present results show that the newly synthesized Cav2-MIF and sLys2-MIF might affect electrically evoked smooth muscle contractions.

Effect of diphenylhydramine on the Tyr-MIF-1 antinociception in rats.

Tyr-MIF-1 is a representative of the MIF's family of endogenous peptides. It has been isolated from bovine hypothalamus and human parietal cortex that suggests its involvement in nociception. Tyr-MIF-1 can bind to the mu-receptors as well as to its specific non-opiate receptors in the brain.

Effects of newly synthesized amino acids containing thiazole residues on electrically evoked smooth muscle contractions.

New amino acids containing thiazole residues have been synthesized and in vitro experiments were performed to study their action on neurotransmission in target tissues with adrenergic and cholinergic neurotransmission. Acetaminothiazoles, structurally related to the novel class, are known to act as H1 agonists, therefore, the effects of the newly synthesized Ala- and Pro-thiazole derivatives on smooth muscle contractile activity were compared to those of histamine (HA). The experiments were carried out on electrically stimulated prostatic part of rat and rabbit vasa deferentia and proximal guinea pig ileum.

[Cys(O2NH2)2]enkephalin analogues and dalargin: selectivity for delta-opioid receptors.

To investigate the structure-activity relationships for potent and selective action of enkephalins at the delta-opioid receptors, two newly synthesized analogues, [Cys(O2NH2)2,Leu5]enkephalin and [Cys(O2NH2)2, Met5] enkephalin and the hexapeptide [D-Ala2,Leu5]enkephalyl-Arg (dalargin) were tested and compared with [Leu5]enkephalin and [Met5]enkephalin, for their effectiveness to inhibit electrically evoked contractions of the mouse vas deferens (predominantly enkephalin-selective delta-opioid receptors) and the guinea pig ileum (mu- and kappa-opioid receptors). The mouse vas deferens assays included evaluation of the effects of opioid agonists on the first, purinergic, and the second, adrenergic, components of electrically evoked biphasic responses (10 Hz and 20 Hz) and on ATP- or noradrenaline-evoked, tetrodotoxin-resistant responses. The opioids tested inhibited in a similar manner: (i) the purinergic and the adrenergic components of the electrically evoked contractions; and (ii) the ATP- and noradrenaline-induced postjunctional responses of the mouse vas deferens.

Dalargin and [Cys-(O2NH2)]2 analogues of enkephalins and their selectivity for mu opioid receptors.

1. Effects of the enkephalins Met-enk (M) and Leu-enk (L), of two newly synthesized analogues--[Cys-(O2NH2)]2-Met-enk (CM) and [Cys-(O2NH2)]2-Leu-enk (CL)--and of a hexapeptide--D-Ala2-Leu5-Arg6 (Dalargin; DL) on the spontaneous and electrically stimulated activity were examined with respect to their selectivity for the mu opioid receptors in the longitudinal layer of guinea pig ileum. 2.

Effects of somatostatin and motilin on the motor and myoelectrical activity of the canine stomach and small intestine in vivo.

The experiments were performed on six starved dogs with chronic fistula in the stomach and small intestine and with chronically implanted electrodes on the smooth-muscle wall of these organs. Motilin (15-25 ng/kg i.v.

Effect of cholecystokinin octapeptide and somatostatin on the motility of guinea pig and canine gallbladder.

Species differences have been observed in the effect of cholecystokinin octapeptide (CCK OP) on the canine and guinea pig gallbladder smooth muscle motility. 1. CCK OP was more potent stimulant in canine than in guinea pig gallbladder smooth muscles.

Mode of action of neurotensin on the spontaneous and electrically-induced contractions of gastric smooth muscle.

Mechanical activity was recorded from muscle preparations isolated from the guinea-pig stomach. Neurotensin (10(-11) M to 10(-7) M) produced dose-dependent tonic contractions and showed a higher affinity but lower efficiency compared to acetylcholine (ACH). Atropine and tetrodotoxin had no effect on the neurotensin responses.

Changes in the conductivity and in the functional refractory period of the atrioventricular node during hypoxia.

The experiments were carried out on preparations from rabbit right atrium, containing the sinoatrial node, the interatrial barrier, the atrioventricular node and the His-bundle. Surface electrodes were used to record the atrial and His-electrograms. The conduction time (AH-interval) was measured and the functional refractory period of the node was determined during normoxia (95% O2, 5% CO2) and hypoxia (30% O2, 65% N2 and 5% CO2) for 45 min.