SEARCH · PubMed Health

Results for “DOMS”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 505 records · Page 28Linked to original sources

PubMed1988

Dopamine acts on acetylation of proopiomelanocortin-derived products in dog pituitary.

The effect of chronic dopaminergic receptor blockade using domperidone (DOM) on the immature dog pituitary content of POMC-related peptides was evaluated. Six immature dogs were treated with DOM for 15 days, 3 times/day, po (3 mg/kg) together with DOM sc (0.6 mg/kg) at 21.00 h. Placebo was administered to six control animals with the same protocol. On the 16th day, the animals were killed, the whole pituitary removed, homogenized, and submitted to reverse-phase HPLC purification prior to radioimmunoassay (RIA) evaluation of beta-endorphin, ACTH and alpha-MSH immunoreactivities (ir). DOM-treated dogs showed a pituitary concentration of beta-EP and ACTH similar to the placebo-treated dogs. The total alpha-MSH ir was similar in both groups and distributed on two main peaks: one corresponding to alpha-MSH and another coeluting with des-acetyl-alpha-MSH [1-13(ACTH)NH2]. However, the percentage of alpha-MSH on total ir in DOM-treated dogs (15.4 +/- 2.6%) was lower than in controls (37.5 +/- 4.5%, P less than 0.01); the corresponding percentage of 1-13(ACTH)NH2 content was 63.0 +/- 3.8% vs 44.7 +/- 3.7%, (P less than 0.01). The alpha-MSH/1-13(ACTH)NH2 ratio was considerably decreased by the treatment (0.25 +/- 0.06 vs 0.89 + 0.15, P less than 0.01). Acetyl beta-EP-like ir was also lower in treated (38.4 + 5.4 fmol/mg) vs control (86.6 + 19.2 fmol/mg, P less than 0.05) animals. These data indicate that the dopaminergic system plays an important role in the control of acetylation processes of POMC-related peptides in the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗

PubMed2006

Nutrient regulation of organic matter decomposition in a tropical rain forest.

Terrestrial biosphere-atmosphere CO2 exchange is dominated by tropical forests, so understanding how nutrient availability affects carbon (C) decomposition in these ecosystems is central to predicting the global C cycle's response to environmental change. In tropical rain forests, phosphorus (P) limitation of primary production and decomposition is believed to be widespread, but direct evidence is rare. We assessed the effects of nitrogen (N) and P fertilization on litter-layer organic matter decomposition in two neighboring tropical rain forests in southwest Costa Rica that are similar in most ways, but that differ in soil P availability. The sites contain 100-200 tree species per hectare and between species foliar nutrient content is variable. To control for this heterogeneity, we decomposed leaves collected from a widespread neotropical species, Brosimum utile. Mass loss during decomposition was rapid in both forests, with B. utile leaves losing >80% of their initial mass in <300 days. High organic matter solubility throughout decomposition combined with high rainfall support a model of litter-layer decomposition in these rain forests in which rapid mass loss in the litter layer is dominated by leaching of dissolved organic matter (DOM) rather than direct CO2 mineralization. While P fertilization did not significantly affect mass loss in the litter layer, it did stimulate P immobilization in decomposing material, leading to increased P content and a lower C:P ratio in soluble DOM. In turn, increased P content of leached DOM stimulated significant increases in microbial mineralization of DOM in P-fertilized soil. These results show that, while nutrients may not affect mass loss during decomposition in nutrient-poor, wet ecosystems, they may ultimately regulate CO2 losses (and hence C storage) by limiting microbial mineralization of DOM leached from the litter layer to soil.

Biodegradation, Environmental↗

PubMed2003

Development and field validation of a predictive copper toxicity model for the green alga Pseudokirchneriella subcapitata.

In this study, the combined effects of pH, water hardness, and dissolved organic carbon (DOC) concentration and type on the chronic (72-h) effect of copper on growth inhibition of the green alga Pseudokirchneriella subcapitata were investigated. Natural dissolved organic matter (DOM) was collected at three sites in Belgium and The Netherlands using reverse osmosis. A full central composite test design was used for one DOM and a subset of the full design for the two other DOMs. For a total number of 35 toxicity tests performed, 72-h effect concentration resulting in 10% growth inhibition (EbC10s) ranged from 14.2 to 175.9 micrograms Cu/L (factor 12) and 72-h EbC50s from 26.9 to 506.8 micrograms Cu/L (factor 20). Statistical analysis demonstrated that DOC concentration, DOM type, and pH had a significant effect on copper toxicity; hardness did not affect toxicity at the levels tested. In general, an increase in pH resulted in increased toxicity, whereas an increase of the DOC concentration resulted in decreased copper toxicity. When expressed as dissolved copper, significant differences of toxicity reduction capacity were noted across the three DOM types tested (up to factor 2.5). When expressed as Cu2+ activity, effect levels were only significantly affected by pH; linear relationships were observed between pH and the logarithm of the effect concentrations expressed as free copper ion activity, that is, log(EbC50Cu2+) and log(EbC10Cu2+): (1) log(EbC50Cu2+)= - 1.431 pH + 2.050 (r2 = 0.95), and (2) log(EbC10cu2+) = -1.140 pH -0.812 (r2 = 0.91). A copper toxicity model was developed by linking these equations to the WHAM V geochemical speciation model. This model predicted 97% of the EbC50dissolved and EbC10dissolved values within a factor of two of the observed values. Further validation using toxicity test results that were obtained previously with copper-spiked European surface waters demonstrated that for 81% of tested waters, effect concentrations were predicted within a factor of two of the observed. The developed model is considered to be an important step forward in accounting for copper bioavailability in natural systems.

Biological Availability↗

PubMed2001

Toxicity of cadmium to Caenorhabditis elegans (Nematoda) in whole sediment and pore water--the ambiguous role of organic matter.

A bioassay using the nematode Caenorhabditis elegans was performed with natural sediment that had been spiked with organic matter (36-117 g total organic carbon/kg dry wt) and cadmium (Cd; 10-1,200 mg/kg wet wt). Whole sediment and pore water were tested to study the influence of particulate organic matter (POM) and dissolved organic matter (DOM) on Cd toxicity and to compare the toxicity of the two sediment phases. Toxicity was measured with nematode growth as test parameter. No toxicity was observed if sediment concentrations of Cd were below concentrations of acid-volatile sulfides (AVS). At higher Cd concentrations, toxicity in whole sediment and pore water increased with increasing organic content. This phenomenon was explained by an increase of DOM concentrations in organically enriched treatments and a resulting solubilization of Cd due to Cd complexation by DOM. Because DOM did not alter the bioavailability of Cd for the nematodes, bacteria, serving as food, might have functioned as vectors for Cd-DOM complexes, so that Cd could have become available in the gut of the nematodes. A higher toxicity in whole sediment compared to in pore water in the organically enriched treatments indicated that POM-bound Cd may have contributed to the toxicity of Cd to C. elegans.

Animals↗

PubMed2002

Validation of a modified flory-huggins concept for description of hydrophobic organic compound sorption on dissolved humic substances.

Sorption coefficients (K(DOC)) on dissolved organic matter (DOM) have been determined by means of solid-phase microextraction (SPME) for hydrophobic organic compounds (HOCs) of various classes, for example, polycyclic aromatic hydrocarbons (PAHs), noncondensed arenes, and alkanes. Relating the K(DOC) values obtained to the octanol-water partition coefficients of the solutes results in class-specific correlations. Obviously, PAHs have a higher affinity to DOM than other HOCs with equal K(OW) values. The different K(DOC) to K(OW) correlations can be combined into one general formula based on a modified Flory-Huggins concept. It permits the calculation of sorption coefficients from the solubility parameters (delta) and K(OW) values of the solutes and the solubility parameter of the sorbent. The latter value, which is specific to the DOM under consideration, can be determined from a single measured sorption coefficient. By applying the proposed Flory-Huggins concept, which is based on the presumption of nonspecific interactions between HOCs and DOM, the different affinities of PAHs, noncondensed arenes, and alkanes to DOM can be accurately predicted.

Adsorption↗

PubMed2003

Measuring the bioavailability of two hydrophobic organic compounds in the presence of dissolved organic matter.

Bioavailability of benzo[a]pyrene (BaP) and 3,3',4,4'-tetrachlorobiphenyl (TCB) was studied in natural lake water containing dissolved organic matter (DOM). Lake water was diluted to give a dissolved organic carbon (DOC) range of 1 to 20 mg/L. Partition coefficients for the model compounds were assessed at different DOM concentrations and over time with three different methods, namely equilibrium dialysis and reverse-phase and liquid-liquid extraction. In addition, biological partition coefficients were estimated from the difference in the bioconcentration of the model compounds in Daphnia magna in the presence and absence of DOM. Results showed that bioavailability of the model compounds was reduced by the presence of DOM. The equilibrium dialysis method gave the best estimates for bioavailability of the model compounds when compared with biologically determined values. Both the reverse-phase and the liquid-liquid extraction overestimated the bioavailable fraction. The more pronounced overestimation of bioavailable fraction of TCB suggested that the sorption of TCB was not only lower but the interaction was also weaker than that of BaP. Increasing DOM concentration produced lower partition coefficients and the effect seemed to be more pronounced when measured by the reverse-phase and the extraction methods.

Animals↗

PubMed2003

Sex differences in delayed onset muscle soreness.

AIM: There is agreement that females report greater pain in response to typical experimental pain stimuli than males. However, investigations of sex differences in the sensation of delayed onset muscle soreness (DOMS) have equivocal RESULTS: The objective of this investigation was to examine sex differences in the pain from DOMS with an adequate sample size, quantification of stimulus intensity, and 2 measures of pain. METHODS: Sixty-seven participants (52% females) completed a 2-session protocol. DOMS was induced using eccentric resistance exercises in the elbow flexors of the non-dominant arm. The intensity of the eccentric contractions was based upon concentric strength. Pain response was measured 48 hrs later. The dependent variables were pressure threshold, which was assessed using a dolorimeter, and pain intensity when the arm was moved through full active range of motion, which was assessed with a visual analog scale. RESULTS: The occurrence of DOMS was confirmed by a decrease in pressure threshold after the eccentric contractions and higher pain intensity in the arm that performed the eccentric contractions than the arm that did not. Females reported lower pain intensities (M=3.41, SD=2.13) compared to males (M=5.12, SD=2.05), but no significant sex difference was found in pressure threshold. CONCLUSION: In this investigation, females reported lower muscle pain intensity than males, but showed no sex difference in pressure threshold. These and previous findings suggest that the detection of a sex difference in muscle pain depends upon the methodology of inducing DOMS and measuring sensation.

Adult↗

PubMed2004

Personal video monitor as an accessory to dental operating microscopes.

OBJECTIVE: The aim of this study was to perform a qualitative assessment of the personal video monitor (PVM) as an accessory to the dental operating microscope (DOM). METHOD AND MATERIALS: The PVM was attached to a color video monitor, which was already attached to a DOM through a beam splitter. One faculty clinician performed a complete oral examination on a patient wearing a binocular inclinable lens adapted to the DOM under different magnifications, while a second faculty watched the procedure simultaneously using a PVM. After completing the examination, the operators exchanged the viewing devices and repeated the procedure. RESULTS: When compared to a standard binocular lens attached to the DOM, the second operator using the PVM had an unencumbered view of his surroundings and was able to make head movements freely. However, when comparing the resolution of the standard binocular lens to the PVM, the binocular lens provided a sharper picture with better illumination, especially when using higher magnification. Statistical analysis was not incorporated, as the goal of this experiment was to qualify rather than quantify the established PVM resolution, in this initial analysis. CONCLUSION: The authors concluded that the PVM attached to the video camera and the DOM allowed a second operator to watch the procedure, and it could be used as an important teaching tool. Another application is that the patient may wear the PVM while the procedure is in progress. However, the resolution in the PVM needs to be significantly improved in order to achieve an adequate level of efficiency in four-handed microdentistry.

Computer Terminals↗

PubMed2005

[Bioleaching of fly ash from municipal solid waste incinerator using sewage sludge and pig manure as culture media].

A mixed culture of Acidihiobacillus ferrooaidans and Acidihiobacillus thiooxidans was used to leach heavy metals from municipal solid waste incineration fly ash (MSWI fly ash). This study explored the possibility of using sewage sludge or pig manure as nutrients for supporting the growth of the leaching bacteria and allowing metal solubilization like a synthetic mineral medium. In contrast to pig manure, there is a high ability for acidification of the fly ash and solubilization of toxic metals using sewage sludge at the same content. After 15 d of bioleaching, the following removal efficiencies were obtained for the treatment with the addition of 1% sewage sludge: Cd 88.1%; Zn 78.7%; Cu 69.6%, whereas their removal efficiencies for the treatment with the addition of 1% pig manure were 82.4%, 73.5% and 60.0%, respectively. Results demonstrate that the inhibition by sewage sludge DOM is much more significant than by pig manure DOM at the same concentration level. The dissolved organic carbon in excess of 400 and 150 mg/L was inhibitory to the bacterial growth using sludge DOM and manure DOM, respectively. Compared with sewage sludge, pig manure contained a higher fraction of DOM with molecular size <1000, which led to its higher toxicity.

Acidithiobacillus↗

PubMed1990

Phenylalkylamine stimulants, hallucinogens, and designer drugs.

Phenylalkylamine derivatives produce several types of behavioral effects including central stimulation and hallucinogenic activity. SAR are being formulated and already (a) it has been demonstrated that each of these types of activities is associated with a distinct SAR, and (b) it is now possible to use these SAR to make predictions as to whether the stimulus effects of certain PAAs are primarily AMPH-like or DOM-like. The AMPH-like nature of PAAs seems to involve a dopaminergic mechanism whereas DOM-like activity involves a serotonergic (in particular a 5-HT2) mechanism. It is apparent, however, that there is an additional type of activity emerging from studies with some PAAs that is neither solely AMPH-like nor DOM-like. MDA seems to produce both types of actions and may even produce this third type of effect. MDMA produces AMPH-like and MDA-like effects, but does not produce DOM-like effects. Other agents, such as MDE and PMMA, produce neither AMPH-like nor DOM-like effects but clearly produce MDMA-like stimulus effects. Thus, there is a third type of SAR that may be formulated. In all likelihood, however, few PAAs will be shown to produce a single "pure" activity and because there are some similarities in the different SARs (even though there are some very clear differences) it is not unreasonable to assume that many PAAs will produce more than one type of effect or will display vestiges of one or more different components of action. Therefore, although a PAA may be classified as primarily producing one type of effect, it should be understood that the other types of effects are not necessarily absent.(ABSTRACT TRUNCATED AT 250 WORDS)

Aniline Compounds↗

PubMed2005

Hallucinogen-like actions of 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7) in mice and rats.

RATIONALE: Few studies have examined the effects of 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7) in vivo. OBJECTIVES: 2C-T-7 was tested in a drug-elicited head twitch assay in mice and in several drug discrimination assays in rats; 2C-T-7 was compared to the phenylisopropylamine hallucinogen R(-)-1-(2,5-dimethoxy-4-methylphenyl)-2aminopropane (DOM) in both assays, with or without pretreatment with the selective 5-HT2A antagonist (+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907). Finally, the affinity of 2C-T-7 for three distinct 5-HT receptors was determined in rat brain. METHODS: Drug-elicited head twitches were quantified for 10 min following administration of various doses of either 2C-T-7 or R(-)-DOM, with and without pretreatments of 0.01 mg/kg M100907. In rats trained to discriminate lysergic acid diethylamide (LSD), 2C-T-7 and R(-)-DOM were tested for generalization. In further studies, rats were trained to discriminate 2C-T-7 from saline, then challenged with 0.05 mg/kg M100907. In competition binding studies, the affinity of 2C-T-7 was assessed at 5-HT2A receptors, 5-HT1A receptors, and 5-HT2C receptors. RESULTS: 2C-T-7 and R(-)-DOM induced similar head twitch responses in the mouse that were antagonized by M100907. In the rat, 2C-T-7 produced an intermediate degree of generalization (75%) to the LSD cue and served as a discriminative stimulus; these interoceptive effects were attenuated by M100907. Finally, 2C-T-7 had nanomolar affinity for 5-HT2A and 5-HT2C receptors and lower affinity for 5-HT1A receptors. CONCLUSIONS: 2C-T-7 is effective in two rodent models of 5-HT2 agonist activity and has affinity at receptors relevant to hallucinogen effects. The effectiveness with which M100907 antagonizes the behavioral actions of 2C-T-7 strongly suggests that the 5-HT2A receptor is an important site of action for this compound.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1982

Neurotransmitter basis of the behavioral effects of hallucinogens.

Indole and phenethylamine-type hallucinogenic drugs were studied in an FR-40 operant behavioral procedure programmed to quantify "pausing,"-a behavioral disruption somewhat specific to hallucinatory drug effects. LSD, DOM, DMT and mescaline showed a potency ratio to produce pausing that is well correlated with the hallucinatory potencies of these agents in man. Furthermore, combinations of the hallucinogens interact with potentiation to cause FR-40 pausing, whereas a variety of non-hallucinogenic psychoactive drugs failed to shift the dose-response patterns of pausing for DOM or LSD. Depletion of brain catecholamines by pretreatment with intraventricular 6-OHDA reduced baseline FR-40 rates and attenuated the disruptive effects of d-amphetamine, but failed to modify the dose-response patterns of indole and phenethylamine hallucinogens. On the other hand, pretreatment with intraventricular 5,7-DHT to deplete brain 5-HT potentiated the pause-producing effects of the hallucinogens, although the disruptive effects of phenobarbital were not altered by this pretreatment. Injection of 5,7-DHT into the medial forebrain bundle at the hypothalamic level slightly potentiated LSD, attenuated DOM, and did not affect the pausing produced by mescaline. Metergoline pretreatment shifted the LSD and DMT dose-response curves for pausing to the right by a factor of 2--3, but shifted the DOM and mescaline dose-response patterns to a much greater extent. Metergoline alone slightly increased FR-40 response rates and decreased pausing from baseline levels. The patterns of imparied FR-40 performance induced by d-amphetamine and phenobarbital were unaltered by pretreatment with metergoline. The indole and phenethylamine classes of hallucinogens appear to disrupt this behavior by an agonistic effect at central 5-HT receptors. However, the two classes of drugs may interact with brain 5-HT systems by somewhat different mechanisms.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1988

Potency of antipsychotics in reversing the effects of a hallucinogenic drug on locus coeruleus neurons correlates with 5-HT2 binding affinity.

Systemic administration of the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) has previously been shown to decrease spontaneous activity but increase the response to peripheral nerve stimulation of locus coeruleus (LC) neurons in anesthetized rats. Five antipsychotic drugs (spiperone, chlorpromazine, clozapine, haloperidol, and sulpiride) were tested for their ability to antagonize these effects of DOM in the LC. Spiperone, chlorpromazine, clozapine, and haloperidol were able to completely reverse the effects of a standard dose of DOM, while sulpiride was ineffective. The ED100s for reversing the effects of DOM showed a significant correlation only with the previously shown binding affinity for 5-HT2 receptors. These results suggest that certain types of antipsychotic drugs have activity as 5-HT2 antagonists in vivo.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1997

Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs.

Structurally, methcathinone is to cathinone what methamphetamine is to amphetamine. Due to increased interest in the abuse of such agents we wished to determine if certain derivatives of cathinone would behave in a manner consistent with what is known about their amphetamine counterparts; that is, can amphetamine structure-activity relationships be extrapolated to cathinone analogs? As expected on the basis of known structure-activity relationships for amphetaminergic agents, both N-monoethylcathinone and N-mono-n-propylcathinone (N-Et CAT and N-Pr CAT; ED50 = 0.77 and 2.03 mg/kg, respectively) produced amphetamine-like stimulus effects in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle and were somewhat less potent than racemic methcathinone. In contrast, (-)N,N-dimethylcathinone or (-)Di Me CAT (ED50 = 0.44 mg/kg) was more potent than expected; although (+)N,N-dimethylamphetamine is sevenfold less potent than (+)methamphetamine, (-)Di Me CAT is only about 1.6-fold less potent than (-)methcathinone, and is essentially equipotent with (-)cathinone. In addition, although it has been previously demonstrated that 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) results in stimulus generalization in rats trained to discriminate (+)amphetamine or DOM from vehicle, the cathinone counterpart of MDA (i.e., MDC) resulted in partial (maximum: 58%) generalization in (+)amphetamine-trained animals, and failed to produce >7% DOM-appropriate responding in rats trained to discriminate DOM from vehicle. On the other hand, the N-methyl analog of MDC (i.e., MDMC) behaved in a manner similar to that of the N-methyl analog of MDA (i.e., MDMA); that is, a (+)amphetamine stimulus (MDMC: ED50 = 2.36 mg/kg) but not a DOM stimulus generalized to MDMC. In MDMA-trained rats, stimulus generalization occured both to MDC and MDMC (ED50 = 1.64 and 1.60 mg/kg, respectively). Although this and previous studies have demonstrated that significant parallelisms exist between the structure-activity relationships of amphetamine analogs and cathinone analogs, we now report several unexpected qualitative and/or quantitative differences. It is suggested that caution be used in attempting to draw conclusions or make predictions about the activity and potency of novel cathinone analogs by analogy to the structure-activity relationships derived from amphetamine-related agents; it would appear that each new cathinone analog will require individual investigation.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1998

Investigation of hallucinogenic and related beta-carbolines.

Certain beta-carbolines are known to be hallucinogenic in humans, and several produce stimulus effects in animals similar to those of the classical hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). Classical hallucinogens bind at 5-HT2 serotonin receptors and these receptors are thought to play a role in their mechanism of action. In the present study, we examined the binding of 15 beta-carbolines at rat 5-HT2A and 5-HT2C receptors. Affinities (Ki values) of the beta-carbolines ranged from about 100 nM to greater than 10,000 nM depending upon the degree of saturation of the pyridyl ring, and upon the presence and location of methoxy substituents in the benzenoid ring. In a further study, six rats were trained to discriminate the hallucinogenic beta-carboline harmaline (3.0 mg/kg, i.p.) from vehicle using a VI-15s schedule of reinforcement. This represents the first time a hallucinogenic beta-carboline has been used as a training drug in a drug discrimination study. Administration of DOM to the harmaline-trained animals resulted in 76% harmaline-appropriate responding at 1.25 mg/kg DOM and disruption of behavior at a higher dose. Taken together, the results of the present investigation demonstrate that: (a) certain beta-carbolines bind at 5-HT2 receptors; (b) that harmaline serves as a training drug at 3.0 mg/kg in drug discrimination studies with rats as subjects; and that (c) there is some similarity between the stimulus effects produced by harmaline and DOM.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1993

Antagonism of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane stimulus with a newly identified 5-HT2- versus 5-HT1C-selective antagonist.

DOM [i.e., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane] is a 5-HT1C/2 serotonin agonist that exerts stimulus control of behavior in animals. In order to determine if the discriminative stimulus effect of DOM is 5-HT1C- or 5-HT2-mediated, it would be informative to conduct tests of stimulus antagonism with a 5-HT1C- or 5-HT2-selective antagonist. To date, no such agents exist. Although the neuroleptic agent spiperone binds at D2 dopamine receptors and 5-HT1A serotonin receptors, (a) it displays about a 1000-fold selectivity for 5-HT2 versus 5-HT1C sites and (b) it has been used as a "5-HT2-selective" antagonist. Because spiperone is a behaviorally disruptive agent, it is not suitable for use in drug-discrimination studies. Using the spiperone molecule as a starting point, a limited structure-affinity investigation was conducted in order to identify a suitable antagonist with high affinity and selectivity for 5-HT2 receptors, and yet an antagonist that might lack the disruptive actions of spiperone. Various modifications of the spiperone molecule were examined, but most resulted in decreased 5-HT2 affinity or in loss of selectivity. One compound, 8-[3-(4-fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]de can-4-on e (26), was shown to bind at 5-HT2 sites with high affinity (Ki = 2 nM) and > 2,000-fold selectivity versus 5-HT1C sites. In tests of stimulus antagonism using rats trained to discriminate 1 mg/kg of DOM from saline vehicle, 26 behaved as a potent antagonist (ED50 = 0.003 mg/kg) and lacked the disruptive effects associated with spiperone. As such, (a) it would appear that the DOM stimulus is primarily a 5-HT2-mediated, and not 5-HT1C-mediated, phenomenon, and (b) compound 26 may find application in other pharmacologic investigations where spiperone may not be a suitable antagonist.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1979

Chemical and biological studies of 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane, an analogue of 6-hydroxydopamine.

Autoxidation of the bis(O-demethyl)-p-hydroquinone metabolite of the psychotomimetic amine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) at pH 7.4 leads exclusively to a bicyclic imino quinone. This imino quinone is a good alkylating agent, forming covalent adducts via 1,4 addition to thiols. The autoxidation appears to be dependent on trace metal catalysis and is dramatically inhibited by components of the 10000g supernatant fraction of rabbit liver homogenates. Incubation of tritium-labeled hydroquinone with bovine serum albumin under oxidizing conditions leads to significant amounts of nonextractable radioactivity which presumably is dependent on imino quinone alkylation of nucleophilic functionalities present on macromolecules. Incubation of tritium-labeled DOM with rabbit microsomes in the presence of NADPH leads to irreversible binding of the label to macromolecular components of the microsomes. Since this binding is NADPH dependent, it is likely that metabolic conversion of DOM to the hydroquinone is involved. The imino quinone oxidation product is highly lypophilic and is capable of crossing the blood-brain barrier. Intravenous administration of tritium-labeled imino quinone to rats resulted in significant nonextractable radioactivity in brain tissue. These properties of the hydroquinone metabolite parallel those reported for the structurally related sympatholytic compound 6-hydroxydopamine and have led to the hypothesis that the psychotomimetic properties of DOM may be mediated through 6-hydroxydopamine-type interactions of the hydroquinone with important macromolecules in the brain.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1989

Involvement of 5-HT2 receptors in the behaviours produced by intrathecal administration of selected 5-HT agonists and the TRH analogue (CG 3509) to rats.

1. The behavioural effects of the intrathecal injection of a thyrotrophin-releasing hormone (TRH) analogue L-orotyl-L-histidyl-prolineamide (CG 3509, 0.5 micrograms), the non-selective 5-HT1 and 5-HT2 receptor agonist 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT, 2-100 micrograms) and the selective 5-HT2 receptor agonist 2,5-dimethoxy-alpha,4-dimethyl-benzene ethamine hydrochloride (DOM, 2-25 micrograms) were compared with the response of systemically administered 5-MeODMT (2 mg kg-1, i.p.) in rats, to establish whether the agonist-induced behaviours were mediated by bulbospinal 5-HT1 or 5-HT2 receptors. 2. Intrathecal injection of 5-MeODMT or DOM produced dose-related back muscle contractions (a previously undocumented behaviour) and wet-dog shakes which were both markedly attenuated by ritanserin pretreatment (1 mg kg-1, i.p.) indicating the involvement of 5-HT2 receptors. In contrast, reciprocal forepaw treading, flat body posture and Straub-tail were evoked by 5-MeODMT but not by DOM indicating that these behaviours were not produced by 5-HT2 receptor activation alone. However, as ritanserin pretreatment reduced the reciprocal forepaw treading induced by intrathecal 5-MeODMT, this behaviour may be facilitated by 5-HT2 receptor activation. 3. Intrathecal 5,7-dihydroxytryptamine (5,7-DHT, 2 x 150 micrograms) treatment decreased thoraco-lumbar spinal cord 5-HT (-95%) and potentiated the back muscle contractions produced by intrathecal DOM injection without altering the wet-dog shake behaviour. None of the components of the 5-HT syndrome produced by 5-MeODMT (2 mg kg-1, i.p.), with the exception of a small increase in wet-dog shakes, was significantly altered by intrathecal 5,7-DHT (which reduced thoraco-lumbar spinal cord 5-HT by 84%). Taken together these data suggest that the only 5-HT agonist-induced behaviour mediated by the activation of 5-HT2 receptors located postsynaptic to bulbospinal 5-hydroxytryptaminergic (5-HTergic) neurones was back muscle contractions. 4. The wet-dog shake and forepaw licking behaviors produced by intrathecal CG 3509 (0.5 micrograms) were attenuated when ritanserin was administered intrathecally 30 min before, but not when it was given at the same time as CG 3509 and neither behaviour was altered by intrathecal 5,7-DHT. This suggests that bulbospinal 5-HTergic neurones are not involved in the production of these TRH analogue-induced behaviours and that the 5-HT2 receptors which mediate these behaviours are not located in the spinal cord.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗