Receptor Agonist Drugs Research Articles

Baclofen for the Treatment of Alcohol Dependence

The amino acid gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the nervous system. The mesolimbic dopamine system is a major component of the brain's reward pathways, and GABA neurons are part of this system, decreasing the activity of dopamine neurons through the inhibitory effects of GABA-B receptors. Because the mesolimbic dopamine system has been linked to the reinforcing effects of alcohol and other drugs of abuse, baclofen (Lioresal(®), Gablofen(®)), a GABA-B receptor agonist drug, has been investigated in preclinical studies as a potential treatment for addictions. Baclofen reduces the reinforcing effects of alcohol and other drugs in animals, providing justification for clinical studies in human beings. Two open-label and two placebo-controlled studies in humans found that baclofen was effective for reducing alcohol craving and intake, but one placebo-controlled study found no benefit for baclofen. Baclofen is a safe and well-tolerated novel drug treatment for alcohol dependence.

Thrombopoietin receptor agonists in refractory immune thrombocytopenia: differential responses to eltrombopag and romiplostim: a case report and possible explanations

Although new thrombopoietin (TPO) receptor agonist drugs, such as romiplostim and eltrombopag, are highly effective and well tolerated for patients with immune thrombocytopenia (ITP) refractory to first-line treatments such as prednisolone, the cross-resistance of these two TPO receptor agonists is still unknown. An 84-year-old Japanese female patient with steroid-refractory ITP received eltrombopag with a gradually increasing dose schedule from 12.5 to 25 mg/day, 37.5 mg/day and finally 50 mg/day. As no increase in platelet count was observed even at the maximum dose of 50 mg/day, and eltrombopag-related grade 3 elevation of aspartate aminotransferase was observed, another TPO receptor agonist, romiplostim, was administered at 1 μg/kg/week subcutaneously. A rapid increase in platelet count was observed 1 week after the first injection. The dose of romiplostim was escalated to 4 μg/kg according to the platelet count and a complete response was achieved 7 weeks after the first injection without any adverse events. The successful treatment of ITP refractory to eltrombopag with romiplostim strongly suggests that the absence of cross-resistance between these two approved TPO receptor agonists and possible differences in mechanism of action. Further study of the mechanisms of action of TPO receptor agonists is called for along with further exploration of the potential of romiplostim in refractory ITP.

Electrically assisted liquid‐phase microextraction for determination of β2‐receptor agonist drugs in wastewater

Electromembrane extraction followed by high-performance liquid chromatography coupled with ultraviolet detection was validated for the determination and quantification of salbutamol (SB) and terbutaline in aqueous samples. A 200-V electrical field was applied to extract the analytes from 2.5 mL sample solution with pH 3.0, through an organic phase which consisted of 80% 2-nitrophenyl octyl ether, 10% di-(2-ethylhexyl) phosphate and 10% tris-(2-ethylhexyl)phosphate as supported liquid membrane into an acidic acceptor solution with pH 1.0, located inside the lumen of a hollow fiber. To achieve the best extraction conditions, the organic membrane composition was optimized separately and other parameters, such as extraction time, applied voltage and pH in sample solution and acceptor phase were studied using experimental design. Under optimal conditions, extraction recoveries of 53 and 43% were obtained for SB and terbutaline, respectively, which corresponded to preconcentration factors of 89 for SB and 72 for terbutaline. The method offers acceptable linearity with correlation coefficient higher than 0.9947 and relative standard deviation less than 4.7%. Finally, it was applied for analysis of drugs in wastewater samples.

Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine

Human xenobiotic-metabolizing cytochrome P450 (CYP) enzymes can each bind and monooxygenate a diverse set of substrates, including drugs, often producing a variety of metabolites. Additionally, a single ligand can interact with multiple CYP enzymes, but often the protein structural similarities and differences that mediate such overlapping selectivity are not well understood. Even though the CYP superfamily has a highly canonical global protein fold, there are large variations in the active site size, topology, and conformational flexibility. We have determined how a related set of three human CYP enzymes bind and interact with a common inhibitor, the muscarinic receptor agonist drug pilocarpine. Pilocarpine binds and inhibits the hepatic CYP2A6 and respiratory CYP2A13 enzymes much more efficiently than the hepatic CYP2E1 enzyme. To elucidate key residues involved in pilocarpine binding, crystal structures of CYP2A6 (2.4 Å), CYP2A13 (3.0 Å), CYP2E1 (2.35 Å), and the CYP2A6 mutant enzyme, CYP2A6 I208S/I300F/G301A/S369G (2.1 Å) have been determined with pilocarpine in the active site. In all four structures, pilocarpine coordinates to the heme iron, but comparisons reveal how individual residues lining the active sites of these three distinct human enzymes interact differently with the inhibitor pilocarpine.

Response Perseveration in Stimulant Dependence Is Associated with Striatal Dysfunction and Can Be Ameliorated by a D2/3 Receptor Agonist

Compulsivity is a hallmark of drug addiction and in animal models is measured by consecutive incorrect responses to a previously rewarded stimulus during reversal learning. The aim of this study was to measure behavioral and neural markers of compulsivity in stimulant-dependent individuals and to test whether these markers could be modulated by treatment with drugs targeting the dopamine system. In a randomized, double-blind, placebo-controlled, crossover design, stimulant-dependent individuals (SDIs; n = 18) and healthy volunteers (n = 18) received single doses of dopamine D(2/3) receptor antagonist (amisulpride, 400 mg) and agonist (pramipexole, 0.5 mg) drugs. To examine compulsivity and its dopaminergic modulation more generally, patients with obsessive-compulsive disorder (OCD; n = 18) were also included in the study. SDIs made significantly more perseverative responses to the previously correct stimulus immediately following reversal, compared with both healthy volunteers and patients with OCD. Across all participants, the number of perseverative errors was negatively correlated with functional activation in right fronto-striato-parietal networks-in particular, the right caudate nucleus. In SDIs, perseveration-related caudate activation was abnormally reduced in the placebo condition, but the dopamine D(2/3) agonist pramipexole normalized both perseverative responding and related activation of the right caudate. Perseveration during reversal learning was associated specifically with stimulant dependence rather than with compulsive behaviors more generally. The beneficial effects of a dopamine agonist drug challenge on both behavior and associated brain activation in SDIs may indicate new avenues for pharmacologic treatment in stimulant dependence.

The Activation of β2-Adrenergic Receptors in Naïve Rats Causes a Reduction of Blood Glutamate Levels: Relevance to Stress and Neuroprotection

This study examines the effects of the activation of β1 and β2-adrenergic receptors on glutamate homeostasis in the blood of naïve rats. Forty five male Sprague-Dawley rats were randomly assigned into one of seven treatment groups that were treated with various β-adrenergic receptor agonist and antagonist drugs. Blood glutamate levels were determined at t=0, 30, 60, 90, and 120min. The activation of β1 and β2-adrenergic receptors via isoproterenol hydrochloride administration produced a marked sustained decrease in blood glutamate levels by 60min after treatment (ANOVA, t=60, 90min: P<0.05, t=120min: P<0.01). Pretreatment with propranolol hydrochloride (a non-selective β-adrenergic receptor blocker) or butaxamine hydrochloride (a selective β2-adrenergic receptor blocker) occluded the isoproterenol-mediated decrease in blood glutamate levels. Propranolol alone had no effect on blood glutamate levels. Selective β1-adrenergic receptor blockade with metoprolol resulted in decreased blood glutamate levels (ANOVA, t=90min: P<0.05, t=120min: P<0.01). Butaxamine hydrochloride alone resulted in a delayed-onset increase in glutamate levels (ANOVA, t=120min: P<0.05). The results suggest that the activation of β2 receptors plays an important role in the homeostasis of glutamate in rat blood.

Potential Adverse Effects of Discontinuing Psychotropic Drugs

For nurses in clinical practice, understanding the pharmacology of drugs their patients take is relevant to understanding their therapeutic uses, side effect profiles, and adverse discontinuation effects. In this article, the last of a four-part series, the discontinuation effects of the following psychotropic drugs are described: benzodiazepine drugs (which have hypnotic, anti-anxiety, and anticonvulsant effects), non-benzodiazepine drugs (used for insomnia), glutamate-modulating drugs, opioid receptor agonist drugs (used as analgesics for the treatment of various pain conditions), and stimulant drugs. Serious adverse effects are likely to occur only after abrupt discontinuation of benzodiazepine drugs, and they should almost always be tapered. Prominent discontinuation effects are seen with opioid and stimulant drugs, but these are usually not serious. Tapering medication, rather than abruptly stopping them, can avoid or minimize the potential adverse discontinuation effects associated with most psychotropic drugs.

Antagonist—agonist combinations as therapies for heroin addiction: back to the future?

Psychopharmacology is a powerful approach to the treatment of many psychiatric disorders. In this article I discuss the conceptual and practical issues in relation to the use of mu opioid receptor agonist, antagonist and partial agonist drugs in the treatment of opioid addiction, as this is one therapeutic area where all three types of agents are currently available. The choice of pharmacological agent is largely determined by patient profile, existence of ongoing drug misuse, and the kinetics of the drugs available. These principles, however, can be applied to other disorders as and when other pharmacological approaches become refined in these areas.

Dose-Response Assay Templates for In vitro Assessment of Resistance to Benzimidazole and Nicotinic Acetylcholine Receptor Agonist Drugs in Human Hookworms

With the implementation of mass drug administration programs for the control of human hookworms, there is a need to monitor for the emergence of drug resistance. We have therefore examined in vitro assays for monitoring sensitivity to benzimidazoles (egg hatch assay) and nicotinic acetylcholine receptor agonist drugs (motility and morphology assays), with a view to developing tools for monitoring drug sensitivity in the field. We have performed assays with Necator americanus and Ancylostoma ceylanicum, and combined this with published data on N. americanus and Ancylostoma caninum, to indicate the breadth of the responses of various hookworm species and isolates in these in vitro assays. This has allowed us to generate assay templates covering the known range of responses, with scope to cover any shift in response that may be indicative of resistance. These assays will have immediate applicability in monitoring for the emergence of drug resistance in human hookworm populations.

Spatial metabolic fingerprinting using FT-IR spectroscopy: investigating abiotic stresses on Micrasterias hardyi

The release of active pharmaceutical ingredients (APIs) into the environment is an ecologically important topic for study because, whilst APIs have been designed to have a wide range of biological properties for the target of interest (usually in man), little information on potential ecological risks is currently available regarding their effects on the organisms that inhabit the environment. In this study, the algae Micrasterias hardyi was exposed to propranolol, metoprolol (beta-adrenergic receptor agonist drugs) and mefenamic acid (a non steroidal anti-inflammatory drug), at concentrations ranging between 0.002-0.2 mM. Initial studies showed that Fourier transform infrared (FT-IR) spectroscopy on algal homogenates illustrated that all three APIs had a quantitative effect on the metabolism of the organisms and it was possible to estimate the level of API exposure from the FT-IR metabolic fingerprints using partial least squares (PLS) regression. From the inspection of the PLS loadings matrices it was possible to elucidate that all drugs caused effects on protein and lipid levels. Most strikingly propranolol had significant effects on the lipid components of the cell. These were dramatically reduced possibly as a consequence of loss of membrane integrity. In order to investigate this further, FT-IR microspectroscopy was used to generate detailed metabolic fingerprinting maps. These chemical maps revealed that all the drugs had a dramatic effect on the distribution of various chemical species throughout the algae, and that all drugs had an affect on protein and lipid levels. In particular, as noted in the PLS analyses for propranolol treated cells, the lipid complement found in the lipid storage areas in the processes of M. hardyi was greatly reduced. This illustrates the power of spatial metabolic fingerprinting for investigating abiotic stresses on complex biological species.

Pathological Gambling Associated With Cabergoline Therapy in a Patient With a Pituitary prolactinoma.

Back to table of contents Previous article Next article LETTERFull AccessPathological Gambling Associated With Cabergoline Therapy in a Patient With a Pituitary prolactinoma.Michael Davie,Michael DavieSearch for more papers by this author,Published Online:1 Oct 2007AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: I report the case of a 47-year-old woman with pathological gambling associated with low dose cabergoline treatment for pituitary prolactinoma. The patient was a previously well woman with no psychiatric history and no previous history of gambling. She was diagnosed with a pituitary prolactinoma at 25 years of age after investigations for infertility and was initially successfully treated with bromocriptine. It was taken for some years and then stopped.At 38 years of age she developed recurrent lactation, ongoing irregular menses and hyperprolactaemia. Repeat MRI confirmed a pituitary microadenoma and cabergoline was commenced at a dose of 0.25 mg weekly. Menses then became regular, galactorrhea improved and prolactin returned to within the normal range. Nausea was reported and surgical treatment offered but declined.Approximately 1 year later she began gambling on poker machines and this behavior escalated over the next 9 years. She gambled on most days and lost approximately $700,000 in total. As her gambling increased she developed depression, paranoia, and marital difficulty. She was commenced on Alendronate sodium at the age of 46 because of osteopenia.At the time of presentation, the diagnoses of major depression with paranoid delusions and pathological gambling were made. Her cabergoline was ceased and an antidepressant, escitalopram was commenced. Two months later her mood had improved, her paranoid delusions had resolved, and her gambling had ceased. Surgical management of her prolactinoma will now be reconsidered. Cabergoline is a dopamine ergoline derivative which stimulates D2 receptors in the pituitary. 1 It has been proposed that pathological gambling is caused by a stimulation of dopaminergic reward systems and is linked with other addictive and obsessive behaviors. 2 Cabergoline has been associated with pathological gambling when used with L -dopa to treat Parkinson’s disease. 3To my knowledge, this is the first report of cabergoline being associated with pathological gambling in a patient with pituitary prolactinoma. Physicians prescribing cabergoline need to be aware of the potential for the development of pathological gambling in their patients.The Hobart Clinic, Rokeby, Tasmania, AustraliaReferences1 . Prescribing Information for cabergoline. eMIMS 2006.Google Scholar2 . Schultz W. Getting formal with dopamine and reward. Neuron 2002; 36:241–263Google Scholar3 . Avanzi M, Uber E, Bonfa F. Pathological gambling in two patients on dopamine replacement therapy for Parkinson’s disease. Neurol Sci 2004; 25:98–101Google Scholar FiguresReferencesCited byDetailsCited ByThe side effects of dopamine receptor agonist drugs in Chinese prolactinoma patients: a cross sectional study11 April 2022 | BMC Endocrine Disorders, Vol. 22, No. 1Impulse control disorders in hyperprolactinemic patients on dopamine agonist therapy20 September 2022 | Reviews in Endocrine and Metabolic Disorders, Vol. 9Binge Eating and Compulsive Buying During Cabergoline Treatment for Prolactinoma: A Case Report26 May 2022 | Frontiers in Psychiatry, Vol. 13Increased prevalence of impulse control disorder symptoms in endocrine diseases treated with dopamine agonists: a cross-sectional study12 December 2020 | Journal of Endocrinological Investigation, Vol. 44, No. 8The risks of medical treatment of prolactinomaAnnales d'Endocrinologie, Vol. 82, No. 1The Journal of Clinical Endocrinology & Metabolism, Vol. 104, No. 7European Journal of EndocrinologyArchives of Endocrinology and Metabolism, Vol. 62, No. 2Annales d'Endocrinologie, Vol. 78Journal of the Neurological Sciences, Vol. 374Clinical Endocrinology, Vol. 86, No. 6Endocrine, Vol. 51, No. 2Asian Journal of Psychiatry, Vol. 22Progress in Neurobiology, Vol. 132Clinical Endocrinology, Vol. 80, No. 6Neurobiology of Disease, Vol. 49Annales d'Endocrinologie, Vol. 73, No. 2Impulse Control Disorders Associated With Dopaminergic Medication in Patients With Pituitary AdenomasClinical Neuropharmacology, Vol. 34, No. 5Medical Journal of Australia, Vol. 190, No. 2 Volume 19Issue 4 Fall, 2007Pages 473-474 Metrics PDF download History Published online 1 October 2007 Published in print 1 October 2007

Alpha-adrenergic mRNA subtype expression in the human nasal turbinate

Alpha-adrenergic receptor (AR) agonist drugs (e.g., epinephrine) are commonly used for upper airway procedures, to shrink the mucosa, retard absorption of local anesthetic agents, and improve visualization by limiting hemorrhage. Decongestant therapy often also includes alphaAR agonist agents, however overuse of these drugs (e.g., oxymetazoline) can result in chronic rhinitis and rebound increases in nasal secretion. Since current decongestants stimulate alphaARs non-selectively, characterization of alphaAR subtype distribution in human airway (nasal turbinate) offers an opportunity to refine therapeutic targets while minimizing side-effects. We, therefore, investigated alphaAR subtype expression in human nasal turbinate within epithelial, duct, gland, and vessel cells using in situ hybridization. Since sensitive and specific anti-receptor antibodies and highly selective alphaAR subtype ligands are currently unavailable, in situ hybridization was performed on sections of three human nasal turbinate samples to identify distribution of alphaAR subtype mRNA. Subtype specific (35)S-labelled mRNA probes were incubated with nasal turbinate sections, and protected fragments remaining after RNase treatment analyzed by light and darkfield microscopy. In non-vascular tissue alpha(1d) AR mRNA predominates, whereas notably the alpha(2c) is the only alphaAR subtype present in the sinusoids and arteriovenous anastamoses. Combined with the current understanding that AR-mediated constriction of nasal sinusoids underpins decongestant therapies that minimize secretions and shrink tissues for airway procedures, these findings suggest that alpha(2c) AR subtypes provide a novel selective target for decongestant therapy in humans.

Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial α7 nicotinic cholinergic agonist drug

(3E)-3-[(2,4-dimethoxyphenyl)methylene]-3,4,5,6-tetrahydro-2,3'-bipyridine (GTS-21), a partial alpha7 nicotinic acetylcholine receptor agonist drug, has recently been shown to improve cognition in schizophrenia and Alzheimer's disease. One of its two major demethylated metabolites, 4-OH-GTS-21, has been suggested to contribute to its therapeutic effects. We labeled GTS-21 in two different positions with carbon-11 ([2-methoxy-(11)C]GTS-21 and [4-(11)C]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy-(11)C]4-OH-GTS-21 and [4-methoxy-(11)C]2-OH-GTS-21) for pharmacokinetic studies in baboons and mice with positron emission tomography (PET). Both [2-(11)C]GTS-21 and [4-methoxy-(11)C]GTS-21 showed similar initial high rapid uptake in baboon brain, peaking from 1 to 3.5 min (0.027-0.038%ID/cc) followed by rapid clearance (t(1/2)<15 min), resulting in low brain retention by 30 min. However, after 30 min, [2-methoxy-(11)C]GTS-21 continued to clear while [4-methoxy-(11)C]GTS-21 plateaued, suggesting the entry of a labeled metabolite into the brain. Comparison of the pharmacokinetics of the two labeled metabolites confirmed expected higher brain uptake and retention of [4-methoxy-(11)C]2-OH-GTS-21 (the labeled metabolite of [4-methoxy-(11)C]GTS-21) relative to [2-methoxy-(11)C]4-OH-GTS-21 (the labeled metabolite of [2-methoxy-(11)C]GTS-21), which had negligible brain uptake. Ex vivo studies in mice showed that GTS-21 is the major chemical form in the mouse brain. Whole-body dynamic PET imaging in baboon and mouse showed that the major route of excretion of C-11 is through the gallbladder. The major findings are as follows: (a) extremely rapid uptake and clearance of [2-methoxy-(11)C]GTS-21 from the brain, which may need to be considered in developing optimal dosing of GTS-21 for patients, and (b) significant brain uptake of 2-OH-GTS-21, suggesting that it might contribute to the therapeutic effects of GTS-21. This study illustrates the value of comparing different label positions and labeled metabolites to gain insight on the behavior of a central nervous system drug and its metabolites in the brain, providing an important perspective on drug pharmacokinetics.

Pramipexole prevents neurotoxicity induced by oligomers of beta-amyloid

Here we demonstrate that pramipexole, an antiparkinsonian dopamine receptor agonist drug, exerts neuroprotective effects against beta-amyloid neurotoxicity. Using a specific protocol to test individually oligomers, fibrils, or unaggregated amyloid beta-peptide, we found pramipexole able to protect cells against oligomers and fibrils. Unaggregated amyloid beta-peptide was found unable to cause cell death. Fibrils and oligomers were also found to produce elevated amount of free radicals, and this effect was prevented by pramipexole. We propose pramipexole may become in the future a coadjuvant in the treatment of neuropathologies, besides Parkinson's disease, where amyloid beta-peptide-mediated oxidative injury exerts a relevant role.

Serotonergic drugs and spinal cord transections indicate that different spinal circuits are involved in external urethral sphincter activity in rats

Lower urinary tract function is regulated by spinal and supraspinal reflexes that coordinate the activity of the urinary bladder and external urethral sphincter (EUS). Two types of EUS activity (tonic and bursting) have been identified in rats. This study in urethane-anesthetized female rats used cystometry, EUS electromyography, spinal cord transection (SCT) at different segmental levels, and analysis of the effects of 5-HT(1A) receptor agonist (8-OH-DPAT) and antagonist (WAY100635) drugs to examine the origin of tonic and bursting EUS activity. EUS activity was elicited by bladder distension or electrical stimulation of afferent axons in the pelvic nerve (pelvic-EUS reflex). Tonic activity evoked by bladder distension was detected in spinal cord-intact rats and after acute and chronic T8-9 or L3-4 SCT but was abolished after L6-S1 SCT. Bursting activity was abolished by all types of SCT except chronic T8-9 transection. 8-OH-DPAT enhanced tonic activity, and WAY100635 reversed the effect of 8-OH-DPAT. The pelvic-EUS reflex consisted of an early response (ER) and late response (LR) when the bladder was distended in spinal cord-intact rats. ER remained after acute or chronic T8-9 and L3-4 SCT, but was absent after L6-S1 SCT. LR occurred only in chronic T8-9 SCT rats where it was enhanced or unmasked by 8-OH-DPAT. The results indicate that spinal serotonergic mechanisms facilitate tonic and bursting EUS activity. The circuitry for generating different patterns of EUS activity appears to be located in different segments of the spinal cord: tonic activity at L6-S1 and bursting activity between T8-9 and L3-4.

The opioid receptor independent actions of kappa receptor agonists in the cardiovascular system.

It is not well known but the actions of opioid receptor agonist and antagonist drugs have not been well characterized in the heart and cardiovascular system. Under normal physiological conditions, opioid receptors have a limited role in the regulation of the cardiovascular system. Instead the primary focus of opioid receptor research, for many years, relates to the characterization of the actions as analgesics in the central nervous system (CNS). Recently, however a series of studies suggest that in particular the arylacetamide class of kappa (kappa) opioid receptor agonist drugs have significant opioid receptor independent actions on the heart and cardiovascular system. Some of the actions of these molecules may indeed be mediated by activation of peripheral opioid receptors; however, these new studies provide pharmacological evidence to the contrary and show using many different in vitro and in vivo animal models that these 'non-opioid' actions result from direct or opioid receptor-independent actions on cardiac tissue. This article will outline the molecular mechanism(s) that are responsible for the cardiovascular and cardiac actions these arylacetamide kappa opioid receptor agonists and characterize the role that these opioid receptors have in ischaemic arrhythmogenesis. In many instances it would appear that the effects of opioid agonists (and antagonists) in cardiovascular disease models of ischaemia may be mediated by opioid receptor-independent actions of these drugs.

Packed column supercritical fluid chromatography of a peroxysome proliferator-activating receptor agonist drug: Achiral and chiral purity of substance, formulation assay and its enantiomeric purity

This paper describes packed column supercritical fluid chromatography (SFC) for the analysis of a peroxysome proliferator-activating γ-receptor agonist that is a carboxylic acid. Evaluation of conditions for the separation of this candidate drug and related compounds in bulk substance is described. A Chiralcel OD column was used for this purpose due to its high selective retention of related substances and relative inertness, though the enantioselectivity was negligible, with methanol as polar modifier. A high enantioselectivity was obtained on Chiralpak AD and it was possible to determine the enantiomeric purity within 10 min on a 5 cm short column. Both the achiral and the chiral systems were run without acid additive in the mobile phase and the level of detection of impurities by area was about 0.1%. For the analysis of samples dissolved in water, without any isolation step, 2-propanol was used as modifier. Due to the column surface activity, evidently generated by injected water, citric acid 1 mM was included as additive in the 2-propanol in order to maintain symmetric and undistorted peak shape. The detection limit for the assay was 21 μg mL −1 (50 nmol mL −1) for 5 μL injected (R.S.D. 6.4 %, n = 8). A 5 cm short Chiralcel OD column was used. Determination of enantiomeric purity of the drug in aqueous samples required increased sensitivity. The sample was acidified and extracted into a small volume of 1-pentanol, out of which 25 μl was analyzed by SFC. The minor enantiomer at the 3% (w/w) level added could be confirmed. Its ratio remained constant during the procedure as measured relative to a reference solution in organic media.

&amp;#946;3-Adrenergic Receptors: Really Relevant Targets for Anti-Obesity Drugs?

In simple terms, obesity is a chronic disorder of energy imbalance, for which a long-term excess of energy intake over expenditure leads to the storage of that excess energy as white adipose tissue. In this article, we review β3- adrenergic receptor agonists, agents in development both to increase energy expenditure and counteract energy expenditure decline following a calorie restriction program. β3- adrenergic receptor agonists are very effective thermogenic anti-obesity and insulin-sensitising agents in rodents. Their main sites of action are white and brown adipose tissue, and muscle. β3-adrenergic receptor mRNA levels are lower in human than in rodent adipose tissue, and adult humans have little brown adipose tissue. Nevertheless, β3-adrenergic receptors are expressed in human white as well as brown adipose tissue and in skeletal muscle, and they play a role in the regulation of energy balance and glucose homeostasis. It is difficult to identify β3-adrenergic receptor agonist drugs because the pharmacology of both β3- and β1- adrenergic receptors can vary. Since their discovery in 1983, hundreds different compounds have been synthesized with β3-adrenergic receptor agonist profile. We identified in the literature 32 molecules in development: 9 molecules are in discovery phase (from 10 October 2001 to 25 November 2002: five molecules in 2002 and 4 in 2001), 5 molecules are in different clinical phases, 10 molecules were discontinued, for 8 molecules no development was reported. Here we have tried to demonstrate that the preclinical and clinical studies on b3-adrenergic receptors and b3-adrenergic receptor agonists as anti-obesity drugs is yet active, even if no conclusive therapeutic agents have been identified. With the huge recent increase in our knowledge on the molecular processes involved in adipose cell biology and adaptive thermogenesis, there may yet be a future for b3-adrenergic receptor agonists. Keywords: adrenergic receptor, adrenergic receptor agonists, thermogenic drugs, energy balance, obesity, brown adipose tissue

New β-adrenergic agonists used illicitly as growth promoters in animal breeding: chemical and pharmacodynamic studies

Clenbuterol and β-adrenergic receptor agonist drugs are illegally used as growth promoters in animal production. Pharmacologically active residues in edible tissues led to intoxication outbreaks in several countries. Pressure of official controls pulsed synthesis of new compounds to escape analytical procedures. We report two new compounds named ‘A’ and ‘G4’, found in feeding stuffs. Chemical structure was studied through nuclear magnetic resonance-imaging and infrared spectroscopy, and β 1- and β 2-adrenergic activity was evaluated on isolated guinea-pig atrium and trachea in comparison with clenbuterol. Both compounds share with clenbuterol an halogenated aromatic ring with a primary amino group. Main modifications consisted of substitution of secondary amino group with an alkyl chain in compound A and substitution of the ter-butyl group with a benzene ring in compound G4. In guinea-pig trachea these compounds showed myorelaxant potency lower than clenbuterol (EC 50 was 43.8 nM for clenbuterol, 11 700 nM for compound A, 2140 nM for G4). On the contrary, in the guinea-pig atrium (heart-beat rate stimulant effect) the compounds were more potent than clenbuterol (EC 50 was 15.2 nM for clenbuterol, 3.4 nM for compound A, 2.8 nM for G4). These pharmacodynamic properties, and stronger lipophilic properties shown by the two compounds may result in increased cardiovascular risk for consumers of illicitly treated animals.

Differing central amine receptor sensitivity in different migraine subtypes? A neuroendocrine study using buspirone

Despite the importance of the 5HT1A receptor in regulating central serotonergic tone, there is a dearth of research examining its role in migraine. In this study, we examined the hypothesis that there would be altered neuroendocrine responses to a 5HT1A agonist challenge in different migraine subtypes. Prolactin (PRL) responses to the 5HT1A receptor agonist drug buspirone were compared in 30 female subjects with migraine (ten migraine with aura, MA; ten migraine without aura, MO and ten chronic/transformed migraine, CM), and ten healthy controls matched for age, gender and menstrual status. None of the subjects were taking psychotropic medication or migraine prophylactic treatment and those with formal psychiatric disorder were excluded. Endocrine responses were determined by measuring differences between baseline PRL and maximum increases post-buspirone (ΔPRL). There was no difference in baseline PRL between groups. MA subjects did not differ in their PRL responses to buspirone compared to healthy controls. The MO group had a four-fold increase in mean ΔPRL responses compared to healthy controls. Mean ΔPRL was also increased in the CM group compared to controls, but the difference was less exaggerated. This study indicates that there is supersensitive central amine receptor function in MO and CM, but not in MA. These findings support the hypothesis that central 5HT function differs among the migraine subtypes. The results also suggest that migrainous ‘transformation’ may be associated with adaptive changes in central 5HT receptor sensitivity. The relative contribution of ‘state’ and ‘trait’ receptor function to these findings as well as the possible role of dopamine receptors is discussed.