A. Bocheva - Academia.edu (original) (raw)
Papers by A. Bocheva
Fitoterapia, 2003
Fractions of methanol, dichloromethane, water extracts and volatiles of Carthamus lanatus aerial ... more 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.
… Rendus de l' …, 2004
... 1]. Kyotorphin (Kyo), Leu-Enkephalin (Leu-enk) and Dalargin (Dala) are well-known and documen... more ... 1]. Kyotorphin (Kyo), Leu-Enkephalin (Leu-enk) and Dalargin (Dala) are well-known and documented opioid peptides [1]. Kyo is synthesized by kyotorphin-synthase [2 ... The effect is Nal-reversible. The effects of Tyr-Cav and L-Cav were more pronounced compared with Kyo ( ...
![Research paper thumbnail of Dalargin and [Cys-(O2NH2)]2 analogues of enkephalins and their selectivity for μ opioid receptors](https://attachments.academia-assets.com/87541667/thumbnails/1.jpg)
](General Pharmacology: The Vascular System, 1995
Effects of the enkephalins Met-enk (M) and Leu-enk (L), of two newly synthesized analogues-[Cys-(... more Effects of the enkephalins Met-enk (M) and Leu-enk (L), of two newly synthesized analogues-[Cys-(O2NH2)]2-Met-enk (CM) and [Cys-(O2 NH2)]2-Leu-enk (CL)-and of a hexapeptide-o-Ala2-Leu~-Arg 6 (Dalargin; DL) on the spontaneous and electrically stimulated activity were examined with respect to their selectivity for the # opioid receptors in the longitudinal layer of guinea pig ileum. 2. M and CM exerted relaxing and contractile effects on the spontaneous contractile activity while L, CL and DL produced only relaxation. The order of potency towards the relaxatory phase was DL > M > CM > L > CL and towards the contractile phase CM > M. 3. The effects of enkephalins on the spontaneous activity were naloxone and TTX sensitive except for the contractile phase of M and CM which persisted in the presence of TTX. NO was not involved in the neurotransmission of the relaxatory responses, while the blockade of ~t and fl adrenoceptors showed the participation of adrenergic mechanisms. Relaxation and contraction induced by enkephalins could not be directly attributed to cholinergic neurotransmission. 4. The naloxone-sensitive and concentration-dependent inhibitory effects of enkephalins and their analogues on the electrically stimulated cholinergic contractions were established. The order of the relative potency of opioids was: DL-3.8; M-1.0; L-0.4; CM-4).01; CL~0.005. 5. These data indicated that the D-Ala 2 substitution and lengthening of the peptide chain by Arg 6 in the molecule of L increased the potency at the/z opiate receptors, while the substitution in position 2 with Cys-(O2NH2) in the molecule of M and L yielded a less potent and selective/~ agonists.
European journal of …, 1996
... 1996) 99108 [Cys( O2NH2) 2]enkephalin analogues and dalargin: selectivity for 6opioid recepto... more ... 1996) 99108 [Cys( O2NH2) 2]enkephalin analogues and dalargin: selectivity for 6opioid receptors Nevena Pencheva *, Adriana Bocheva, Emil Dimitrov, Christina ... assay and in mouse vas deferens assay, as compared to the inhibitory effect of [LeuS]enkephalin (Corbett et al ...
European Journal of Pharmacology, 1996
To investigate the structure-activity relationships for potent and selective action of enkephalin... more 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. Extremely low IC50 values (of 2-5 orders) were found for [Cys(O2NH2)2,Leu5] enkephalin, whose relative potency was between 239 and 1316 times higher than that of [Leu5]enkephalin. The order of potency for the other peptides in this tissue was: [Cys(O2NH2)2,Met5]enkephalin > [Leu5]enkephalin > dalargin > [Met5]enkephalin. The highest IC50 values in the guinea pig ileum assays, indicating the lowest affinity for mu-/kappa-opioid receptors, were obtained for the cysteine sulfonamide analogues, while dalargin showed a potency four times higher than that of [Met5]enkephalin. The order of potency in this tissue was: dalargin > [Met5]enkephalin > [Leu5]enkephalin > [Cys(O2NH2)2,Met5]enkephalin > [Cys(O2NH2)2,Leu5]enkephalin. The ratio, IC50 in guinea pig ileum: IC50 in mouse vas deferens, indicating selectivity of the respective peptide for delta-opioid receptors, was extremely high for [Cys(O2NH2)2,Leu5]enkephalin and especially for the adrenergic component of the responses. This ratio for [Cys(O2NH2)2,Met5]enkephalin was higher than the ratios for dalargin, [Leu5]enkephalin and [Met5]enkephalin, which were about 3 orders of magnitude lower. The results suggest that incorporation of hydrophilic Cys(O2NH2) in the enkephalin molecule greatly increases the potency and selectivity of the analogues at delta-opioid receptors, while both D-Ala2 substitution and lengthening of the peptide chain by Arg6 in the molecule of [Leu5]enkephalin decrease them.
Dokladi na B lgarskata …, 2008
One of the mechanisms known to play a part in the response of an organism to stress is activation... more One of the mechanisms known to play a part in the response of an organism to stress is activation of the endogenous opioid system. Endogenous opioid peptides take part in various functions as hormones or neuromodulators. In 1979 Takagi and his co-workers identified a new morphine-like substance-"kyotorphin". Kyotorphin (Kyo) may possess properties of neuromediator/neuromodulator. Moderate concentrations of kyotorphin are present in the hypothalamus, one of the central control stations of the stress system, which coordinates the adaptive responses of the organism to stressors of any kind, including cold environment. Literature data showed that Kyo administered intracerebroventrucular increased plasma levels of oxytocin-"stress" hormone in rodents. Literature data revealed that stress caused the activation of NO-producing neurons. Nitric oxide (NO) is involved in NO-molecular ways, which affect through auto regulation different signalling molecules, like opioids, endocanabiotics and others. Also, it is known that Kyo, as well as L-arginine, are possible substrates for inducible and neuronal nitric oxide synthase. The aim of our study was to investigate the effect of Kyo (5 mg/kg, i.p.) on NO activity in rat hypothalamic paraventricular nucleus (PVN) after 1 h cold stress. A histochemical procedure for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-reactive neurons was used in male Wistar rats. Our results showed that NADPH-d reactive neurons in rat hypothalamus were increased by cold stress and affected by Kyo. To our knowledge, this is the first report showing that kyotorphin can increased NO activity in hypothalamic PVN in cold exposed rats.
Autonomic & Autacoid Pharmacology, 2007
1 Tyr-K-MIF-1 is a melanocyte inhibiting factor (MIF) neuropeptide, isolated from the brain. Oppo... more 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 lreceptors, but interacts with Tyr-MIF-1 specific binding sites. Tyr-MIF-1 and Tyr-W-MIF-1 evoke antinociception mainly by activating opioid receptors. We investigated the possible antinociceptive effect of Tyr-K-MIF-1 and the involvement of histaminergic system in its mechanism of action. 2 Tested on rats by paw-pressure test, Tyr-K-MIF-1 (0.5, 1 and 2 mg kg)1) was associated with short-lasting analgesia, which was abolished by naloxone (1 mg kg)1). 3 Injected intraperitoneally (i.p.) 15 min before Tyr-K-MIF-1, antagonists of H 1 (diphenhydramine, 100 mg kg)1) or H 2 (famotidine, 0.3 and 0.6 mg kg)1) histamine receptors diminished peptide antinociceptive effect. Simultaneous H 1-and H 2 blockade, as well as pretreatment with 5 mg kg)1 dimaprit (H 2 agonist) abolished Tyr-K-MIF-1-induced analgesia. Tyr-K-MIF-1-induced analgesia was also abolished by treatment with R-(a)-methylhistamine (10 mg kg)1 , i.p.), an H 3 histamine receptor agonist that acts to inhibit histamine release. 4 Our results together with data reported in the literature support the conclusion that activation of the histaminergic system is involved in the mechanism of Tyr-K-MIF-1-induced antinociception.
![Research paper thumbnail of Dalargin and [Cys-(O2NH2)]2 analogues of enkephalins and their selectivity for μ opioid receptors](https://attachments.academia-assets.com/42222666/thumbnails/1.jpg)
](General Pharmacology: The Vascular System, 1995
1. Effects of the enkephalins Met-enk (M) and Leu-enk (L), of two newly synthesized analogues--[C... more 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. M and CM exerted relaxing and contractile effects on the spontaneous contractile activity while L, CL and DL produced only relaxation. The order of potency towards the relaxatory phase was DL > M > CM > L > CL and towards the contractile phase CM > M. 3. The effects of enkephalins on the spontaneous activity were naloxone and TTX sensitive except for the contractile phase of M and CM which persisted in the presence of TTX. NO was not involved in the neurotransmission of the relaxatory responses, while the blockade of alpha and beta adrenoceptors showed the participation of adrenergic mechanisms. Relaxation and contraction induced by enkephalins could not be directly attributed to cholinergic neurotransmission. 4. The naloxone-sensitive and concentration-dependent inhibitory effects of enkephalins and their analogues on the electrically stimulated cholinergic contractions were established. The order of the relative potency of opioids was: DL-3.8; M-1.0; L-0.4; CM-0.01; CL-0.005. 5. These data indicated that the D-Ala2 substitution and lengthening of the peptide chain by Arg6 in the molecule of L increased the potency at the mu opiate receptors, while the substitution in position 2 with Cys-(O2NH2) in the molecule of M and L yielded a less potent and selective mu agonists.
Fitoterapia, 2003
Fractions of methanol, dichloromethane, water extracts and volatiles of Carthamus lanatus aerial ... more 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.
… Rendus de l' …, 2004
... 1]. Kyotorphin (Kyo), Leu-Enkephalin (Leu-enk) and Dalargin (Dala) are well-known and documen... more ... 1]. Kyotorphin (Kyo), Leu-Enkephalin (Leu-enk) and Dalargin (Dala) are well-known and documented opioid peptides [1]. Kyo is synthesized by kyotorphin-synthase [2 ... The effect is Nal-reversible. The effects of Tyr-Cav and L-Cav were more pronounced compared with Kyo ( ...
General Pharmacology: The Vascular System, 1995
Effects of the enkephalins Met-enk (M) and Leu-enk (L), of two newly synthesized analogues-[Cys-(... more Effects of the enkephalins Met-enk (M) and Leu-enk (L), of two newly synthesized analogues-[Cys-(O2NH2)]2-Met-enk (CM) and [Cys-(O2 NH2)]2-Leu-enk (CL)-and of a hexapeptide-o-Ala2-Leu~-Arg 6 (Dalargin; DL) on the spontaneous and electrically stimulated activity were examined with respect to their selectivity for the # opioid receptors in the longitudinal layer of guinea pig ileum. 2. M and CM exerted relaxing and contractile effects on the spontaneous contractile activity while L, CL and DL produced only relaxation. The order of potency towards the relaxatory phase was DL > M > CM > L > CL and towards the contractile phase CM > M. 3. The effects of enkephalins on the spontaneous activity were naloxone and TTX sensitive except for the contractile phase of M and CM which persisted in the presence of TTX. NO was not involved in the neurotransmission of the relaxatory responses, while the blockade of ~t and fl adrenoceptors showed the participation of adrenergic mechanisms. Relaxation and contraction induced by enkephalins could not be directly attributed to cholinergic neurotransmission. 4. The naloxone-sensitive and concentration-dependent inhibitory effects of enkephalins and their analogues on the electrically stimulated cholinergic contractions were established. The order of the relative potency of opioids was: DL-3.8; M-1.0; L-0.4; CM-4).01; CL~0.005. 5. These data indicated that the D-Ala 2 substitution and lengthening of the peptide chain by Arg 6 in the molecule of L increased the potency at the/z opiate receptors, while the substitution in position 2 with Cys-(O2NH2) in the molecule of M and L yielded a less potent and selective/~ agonists.
European journal of …, 1996
... 1996) 99108 [Cys( O2NH2) 2]enkephalin analogues and dalargin: selectivity for 6opioid recepto... more ... 1996) 99108 [Cys( O2NH2) 2]enkephalin analogues and dalargin: selectivity for 6opioid receptors Nevena Pencheva *, Adriana Bocheva, Emil Dimitrov, Christina ... assay and in mouse vas deferens assay, as compared to the inhibitory effect of [LeuS]enkephalin (Corbett et al ...
European Journal of Pharmacology, 1996
To investigate the structure-activity relationships for potent and selective action of enkephalin... more 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. Extremely low IC50 values (of 2-5 orders) were found for [Cys(O2NH2)2,Leu5] enkephalin, whose relative potency was between 239 and 1316 times higher than that of [Leu5]enkephalin. The order of potency for the other peptides in this tissue was: [Cys(O2NH2)2,Met5]enkephalin > [Leu5]enkephalin > dalargin > [Met5]enkephalin. The highest IC50 values in the guinea pig ileum assays, indicating the lowest affinity for mu-/kappa-opioid receptors, were obtained for the cysteine sulfonamide analogues, while dalargin showed a potency four times higher than that of [Met5]enkephalin. The order of potency in this tissue was: dalargin > [Met5]enkephalin > [Leu5]enkephalin > [Cys(O2NH2)2,Met5]enkephalin > [Cys(O2NH2)2,Leu5]enkephalin. The ratio, IC50 in guinea pig ileum: IC50 in mouse vas deferens, indicating selectivity of the respective peptide for delta-opioid receptors, was extremely high for [Cys(O2NH2)2,Leu5]enkephalin and especially for the adrenergic component of the responses. This ratio for [Cys(O2NH2)2,Met5]enkephalin was higher than the ratios for dalargin, [Leu5]enkephalin and [Met5]enkephalin, which were about 3 orders of magnitude lower. The results suggest that incorporation of hydrophilic Cys(O2NH2) in the enkephalin molecule greatly increases the potency and selectivity of the analogues at delta-opioid receptors, while both D-Ala2 substitution and lengthening of the peptide chain by Arg6 in the molecule of [Leu5]enkephalin decrease them.
Dokladi na B lgarskata …, 2008
One of the mechanisms known to play a part in the response of an organism to stress is activation... more One of the mechanisms known to play a part in the response of an organism to stress is activation of the endogenous opioid system. Endogenous opioid peptides take part in various functions as hormones or neuromodulators. In 1979 Takagi and his co-workers identified a new morphine-like substance-"kyotorphin". Kyotorphin (Kyo) may possess properties of neuromediator/neuromodulator. Moderate concentrations of kyotorphin are present in the hypothalamus, one of the central control stations of the stress system, which coordinates the adaptive responses of the organism to stressors of any kind, including cold environment. Literature data showed that Kyo administered intracerebroventrucular increased plasma levels of oxytocin-"stress" hormone in rodents. Literature data revealed that stress caused the activation of NO-producing neurons. Nitric oxide (NO) is involved in NO-molecular ways, which affect through auto regulation different signalling molecules, like opioids, endocanabiotics and others. Also, it is known that Kyo, as well as L-arginine, are possible substrates for inducible and neuronal nitric oxide synthase. The aim of our study was to investigate the effect of Kyo (5 mg/kg, i.p.) on NO activity in rat hypothalamic paraventricular nucleus (PVN) after 1 h cold stress. A histochemical procedure for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-reactive neurons was used in male Wistar rats. Our results showed that NADPH-d reactive neurons in rat hypothalamus were increased by cold stress and affected by Kyo. To our knowledge, this is the first report showing that kyotorphin can increased NO activity in hypothalamic PVN in cold exposed rats.
Autonomic & Autacoid Pharmacology, 2007
1 Tyr-K-MIF-1 is a melanocyte inhibiting factor (MIF) neuropeptide, isolated from the brain. Oppo... more 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 lreceptors, but interacts with Tyr-MIF-1 specific binding sites. Tyr-MIF-1 and Tyr-W-MIF-1 evoke antinociception mainly by activating opioid receptors. We investigated the possible antinociceptive effect of Tyr-K-MIF-1 and the involvement of histaminergic system in its mechanism of action. 2 Tested on rats by paw-pressure test, Tyr-K-MIF-1 (0.5, 1 and 2 mg kg)1) was associated with short-lasting analgesia, which was abolished by naloxone (1 mg kg)1). 3 Injected intraperitoneally (i.p.) 15 min before Tyr-K-MIF-1, antagonists of H 1 (diphenhydramine, 100 mg kg)1) or H 2 (famotidine, 0.3 and 0.6 mg kg)1) histamine receptors diminished peptide antinociceptive effect. Simultaneous H 1-and H 2 blockade, as well as pretreatment with 5 mg kg)1 dimaprit (H 2 agonist) abolished Tyr-K-MIF-1-induced analgesia. Tyr-K-MIF-1-induced analgesia was also abolished by treatment with R-(a)-methylhistamine (10 mg kg)1 , i.p.), an H 3 histamine receptor agonist that acts to inhibit histamine release. 4 Our results together with data reported in the literature support the conclusion that activation of the histaminergic system is involved in the mechanism of Tyr-K-MIF-1-induced antinociception.
General Pharmacology: The Vascular System, 1995
1. Effects of the enkephalins Met-enk (M) and Leu-enk (L), of two newly synthesized analogues--[C... more 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. M and CM exerted relaxing and contractile effects on the spontaneous contractile activity while L, CL and DL produced only relaxation. The order of potency towards the relaxatory phase was DL > M > CM > L > CL and towards the contractile phase CM > M. 3. The effects of enkephalins on the spontaneous activity were naloxone and TTX sensitive except for the contractile phase of M and CM which persisted in the presence of TTX. NO was not involved in the neurotransmission of the relaxatory responses, while the blockade of alpha and beta adrenoceptors showed the participation of adrenergic mechanisms. Relaxation and contraction induced by enkephalins could not be directly attributed to cholinergic neurotransmission. 4. The naloxone-sensitive and concentration-dependent inhibitory effects of enkephalins and their analogues on the electrically stimulated cholinergic contractions were established. The order of the relative potency of opioids was: DL-3.8; M-1.0; L-0.4; CM-0.01; CL-0.005. 5. These data indicated that the D-Ala2 substitution and lengthening of the peptide chain by Arg6 in the molecule of L increased the potency at the mu opiate receptors, while the substitution in position 2 with Cys-(O2NH2) in the molecule of M and L yielded a less potent and selective mu agonists.