Antagonist Action (antagonist + action)

Distribution by Scientific Domains


Selected Abstracts


Clinical issues in using buprenorphine in the treatment of opiate dependence

DRUG AND ALCOHOL REVIEW, Issue 3 2000
Dr A. Chadderton MB
Abstract This paper looks at the current role of buprenorphine in the treatment of opiate dependence. It suggests that buprenorphine is a useful alternative to methadone and that in at least some cases it may be the preferred option. Buprenorphineis a partial agonist and a partial antagonist with a ceiling of opiate activity probably approximately equal to 30mg methadone. It achieves this at a dose of 10-12mg, although there is considerable individual variation. Because of its ceiling effect it has a good safety profile compared to full agonists such as methadone although some overdose deaths, particularly in conjunction with benzodiazepine abuse, have been reported in France. Induction of buprenorphine may take slightly longer than for methadone and there is a higher dropout rate compared to methadone in the first 2 weeks. This is probably due to the antagonist action of buprenorphine causing more withdrawal symptoms in comparison to methadone. Also, the ceiling effect for buprenorphine means that some clients do not experience sufficient opiate activity to satisfy them. Buprenorphine has a long half-life and dissociates slowly from opiate receptors. Most clients can be dosed second-daily but some find this unacceptable due to mood swings and/or withdrawal symptomson the second day. For these clients daily dosing is required. Transferring from buprenorphine to methadone is straightforward and well tolerated by clients. Transferring from methadone to buprenorphine, however, is more difficult because of the partial antagonist action of buprenorphine. Clients experience withdrawal symptoms that can take up to 2 weeks to settle. Most clients find these symptoms unacceptable when transferring from doses of over 30mg of methadone. The optimum method for transferring from methadone to buprenorphine is still to be determined. Withdrawal from buprenorphine appears to be relatively easier than from methadone. This is presumably due to buprenorphine's partial agonist effect at mureceptors. It is expected that during 2000 buprenorphine will be approved for use in Australia for the treatment of opiate dependence. It may well becomea first-line choice for opiate replacement in heroin dependence. It is also likely to be useful in assisting detoxification fromboth methadone and heroin. [source]


A cocaine insensitive chimeric insect serotonin transporter reveals domains critical for cocaine interaction

FEBS JOURNAL, Issue 16 2002
Sumandeep K. Sandhu
Serotonin transporters are key target sites for clinical drugs and psychostimulants, such as fluoxetine and cocaine. Molecular cloning of a serotonin transporter from the central nervous system of the insect Manduca sexta enabled us to define domains that affect antagonist action, particularly cocaine. This insect serotonin transporter transiently expressed in CV-1 monkey kidney cells exhibits saturable, high affinity Na+ and Cl, dependent serotonin uptake, with estimated Km and Vmax values of 436 ± 19 nm and 3.8 ± 0.6 × 10,18 mol·cell·min,1, respectively. The Manduca high affinity Na+/Cl, dependent transporter shares 53% and 74% amino acid identity with the human and fruit fly serotonin transporters, respectively. However, in contrast to serotonin transporters from these two latter species, the Manduca transporter is inhibited poorly by fluoxetine (IC50 = 1.23 µm) and cocaine (IC50 = 12.89 µm). To delineate domains and residues that could play a role in cocaine interaction, the human serotonin transporter was mutated to incorporate unique amino acid substitutions, detected in the Manduca homologue. We identified a domain in extracellular loop 2 (amino acids 148,152), which, when inserted into the human transporter, results in decreased cocaine sensitivity of the latter (IC50 = 1.54 µm). We also constructed a number of chimeras between the human and Manduca serotonin transporters (hSERT and MasSERT, respectively). The chimera, hSERT1,146/MasSERT106,587, which involved N-terminal swaps including transmembrane domains (TMDs) 1 and 2, was remarkably insensitive to cocaine (IC50 = 180 µm) compared to the human (IC50 = 0.431 µm) and Manduca serotonin transporters. The chimera MasSERT1,67/hSERT109,630, which involved only the TMD1 swap, showed greater sensitivity to cocaine (IC50 = 0.225 µm) than the human transporter. Both chimeras showed twofold higher serotonin transport affinity compared to human and Manduca serotonin transporters. Our results show TMD1 and TMD2 affect the apparent substrate transport and antagonist sensitivity by possibly providing unique conformations to the transporter. The availability of these chimeras facilitates elucidation of specific amino acids involved in interactions with cocaine. [source]


Interaction of p53 with Mdm2 and azurin as studied by atomic force spectroscopy

JOURNAL OF MOLECULAR RECOGNITION, Issue 4 2010
Gloria Funari
Abstract Azurin, a bacterial protein, can be internalized in cancer cells and induce apoptosis. Such anticancer effect is coupled to the formation of a complex with the tumour-suppressor p53. The mechanism by which azurin stabilizes p53 and the binding sites of their complex are still under investigation. It is also known that the predominant mechanism for p53 down-regulation implies its association to Mdm2, the main ubiquitin ligase affecting its stability. However, the p53/Mdm2 interaction, occurring at the level of both their N-terminal domains, has been characterized so far by experiments involving only partial domains of these proteins. The relevance of the p53/Mdm2 complex as a possible target of the anticancer therapies requires a deeper study of this complex as made up of the two entire proteins. Moreover, the apparent antagonist action of azurin against Mdm2, with respect of p53 regulation, might suggest the possibility that azurin binds p53 at the same site of Mdm2, preventing in such a way p53 and Mdm2 from association and thus p53 from degradation. By following the interaction of the two entire proteins by atomic force spectroscopy, we have assessed the formation of a specific complex between p53 and Mdm2. We found for it a binding strength and a dissociation rate constant typical of dynamical protein,protein interactions and we observed that azurin, even if capable to bind p53, does not compete with Mdm2 for the same binding site on p53. The formation of the p53/Mdm2/azurin ternary complex might suggest an alternative anti-cancer mechanism adopted by azurin. Copyright © 2009 John Wiley & Sons, Ltd. [source]


MULTIDISCIPLINARY PAIN ABSTRACTS: 34

PAIN PRACTICE, Issue 1 2004
Article first published online: 15 MAR 200
Because recent studies emphasized the role of peripherally distributed N-methyl-D-aspartate (NMDA) receptors in processing the nociceptive information, the authors investigated whether peripheral application of the ointment containing ketoconazole (KET) is able to attenuate the symptoms of local neuropathic pain. They applied ointment containing KET (0.25%,1.5%) to the affected area on limbs in five patients with complex regional pain syndrome type I (CRPS I) and in two patients with type II (CRPS II). One to 2 weeks later, they observed improvement of the report of pain intensity, measured by the visual analog scale, in four patients with acute early dystrophic stage of CRPS I. Swelling of the affected limbs subsided as well. No apparent changes were noticed in one patient with chronic atrophic stage of CRPS I and in both patients with CRPS II. The authors concluded that topical application of KET appears to be beneficial for the patients with acute early dystrophic stage of CRPS I because of either its local anesthetic effect or NMDA receptor antagonist action. Patients with chronic atrophic stage of CRPS I and CRPS II patients do not appear to respond to this treatment. [source]


Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of ,2 -adrenergic and serotonin2C receptors: a comparison with citalopram

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2000
M. J. Millan
Abstract Mirtazapine displayed marked affinity for cloned, human ,2A -adrenergic (AR) receptors at which it blocked noradrenaline (NA)-induced stimulation of guanosine-5,-O-(3-[35S]thio)-triphosphate ([35S]-GTP,S) binding. Similarly, mirtazapine showed high affinity for cloned, human serotonin (5-HT)2C receptors at which it abolished 5-HT-induced phosphoinositide generation. Alpha2 -AR antagonist properties were revealed in vivo by blockade of UK-14,304-induced antinociception, while antagonist actions at 5-HT2C receptors were demonstrated by blockade of Ro 60 0175-induced penile erections and discriminative stimulus properties. Mirtazapine showed negligible affinity for 5-HT reuptake sites, in contrast to the selective 5-HT reuptake inhibitor, citalopram. In freely moving rats, in the dorsal hippocampus, frontal cortex (FCX), nucleus accumbens and striatum, citalopram increased dialysate levels of 5-HT, but not dopamine (DA) and NA. On the contrary, mirtazapine markedly elevated dialysate levels of NA and, in FCX, DA, whereas 5-HT was not affected. Citalopram inhibited the firing rate of serotonergic neurons in dorsal raphe nucleus, but not of dopaminergic neurons in the ventral tegmental area, nor adrenergic neurons in the locus coeruleus. Mirtazapine, in contrast, enhanced the firing rate of dopaminergic and adrenergic, but not serotonergic, neurons. Following 2 weeks administration, the facilitatory influence of mirtazapine upon dialysate levels of DA and NA versus 5-HT in FCX was maintained, and the influence of citalopram upon FCX levels of 5-HT versus DA and NA was also unchanged. Moreover, citalopram still inhibited, and mirtazapine still failed to influence, dorsal raphe serotonergic neurons. In conclusion, in contrast to citalopram, mirtazapine reinforces frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission. These actions reflect antagonist properties at ,2A -AR and 5-HT2C receptors. [source]


Gene regulation of ,4,2 nicotinic receptors: microarray analysis of nicotine-induced receptor up-regulation and anti-inflammatory effects

JOURNAL OF NEUROCHEMISTRY, Issue 3 2009
Vishnu Hosur
Abstract ,4,2 Nicotinic acetylcholine receptors play an important role in the reward pathways for nicotine. We investigated whether receptor up-regulation of ,4,2 nicotinic acetylcholine receptors involves expression changes for non-receptor genes. In a microarray analysis, 10 ,M nicotine altered expression of 41 genes at 0.25, 1, 8 and 24 h in h,4,2 SH-EP1 cells. The maximum number of gene changes occurred at 8 h, around the initial increase in 3[H]-cytisine binding. Quantitative RT-PCR corroborated gene induction of endoplasmic reticulum proteins CRELD2, PDIA6, and HERPUD1, and suppression of the pro-inflammatory cytokines IL-1, and IL-6. Nicotine suppresses IL-1, and IL-6 expression at least in part by inhibiting NF,B activation. Antagonists dihydro-,-erythroidine and mecamylamine blocked these nicotine-induced changes showing that receptor activation is required. Antagonists alone or in combination with nicotine suppressed CRELD2 message while increasing ,4,2 binding. Additionally, small interfering RNA knockdown of CRELD2 increased basal ,4,2 receptor expression, and antagonists decreased CRELD2 expression even in the absence of ,4,2 receptors. These data suggest that endoplasmic reticulum proteins such as CRELD2 can regulate ,4,2 expression, and may explain antagonist actions in nicotine-induced receptor up-regulation. Further, the unexpected finding that nicotine suppresses inflammatory cytokines suggests that nicotinic ,4,2 receptor activation promotes anti-inflammatory effects similar to ,7 receptor activation. [source]