α2-Adrenergic agonists as analgesic agents

α₂-Adrenergic agonists are responsible for a variety of physiological responses including analgesia. A total of 16 new chemical series that provide analgesia through an α₂-adrenergic mechanism have been patented since 1997. There were also nine patents issued for known α₂-adrenergic agonists, which have found new application as effective analgesic agents with a diminished side effect profile, such as use in combination with other analgesic agents or through specific routes of administration.     

α2-Adrenoceptors are targets for antipsychotic drugs

Rationale

Almost all antipsychotic drugs (APDs), irrespective of whether they belong to the first-generation (e.g. haloperidol) or second-generation (e.g. clozapine), are dopamine D₂ receptor antagonists. Second-generation APDs, which differ from first-generation APDs in possessing a lower propensity to induce extrapyramidal side effects, target a variety of monoamine receptors such as serotonin (5-hydroxytryptamine) receptors (e.g. 5-HT_1A, 5-HT_2A, 5-HT_2C, 5-HT₆, 5-HT₇) and α₁- and α₂-adrenoceptors in addition to their antagonist effects at D₂ receptors.

Objective

This short review is focussed on the potential role of α₂-adrenoceptors in the antipsychotic therapy.

Results

Schizophrenia is characterised by three categories of symptoms: positive symptoms, negative symptoms and cognitive deficits. α₂-Adrenoceptors are classified into three distinct subtypes in mammals, α_2A, α_2B and α_2C. Whereas the α_2B-adrenoceptor seems to play only a minor role in the brain, activation of postsynaptic α_2A-adrenoceptors in the prefrontal cortex improves cognitive functions. Preclinical models such as D-amphetamine-induced locomotion, the conditioned avoidance response and the pharmacological N-methyl-d-aspartate receptor hypofunction model have shown that α_2C-adrenoceptor blockade or the combination of D₂ receptor antagonists with idazoxan (α_2A/2C-adrenoceptor antagonist) could be useful in schizophrenia. A potential benefit of a treatment combination of first-generation APDs with the α_2A/2C-adrenoceptor antagonists idazoxan or mirtazapine was also demonstrated in patients with schizophrenia.

Conclusions

It is concluded that α₂-adrenoceptors may be promising targets in the antipsychotic therapy.     

Mitochondria targeting drugs for neurodegenerative diseases—Design,mechanism and application

Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons. NDDs threaten the lives of millions of people worldwide and regretfully remain incurable. It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs. Dysfunction of mitochondria results in energy depletion, oxidative stress, calcium overloading, caspases activation, which dominates the neuronal death of NDDs. Therefore, mitochondria are the preferred target for intervention of NDDs. So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome, though there are still some obstacles such as targeting specificity, delivery capacity hindering the drugs development. In present review, we will elaborately address 1) the strategy to design mitochondria targeting drugs, 2) the rescue mechanism of respective mitochondria targeting drugs, 3) how to evaluate the therapeutic effect. Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.     

α-Adrenergic agents. 3. Behavioral effects of 2-aminotetralins

Studies with 5-substituted-8-methoxy-2-aminotetralin compounds suggest that some are ₁-adrenoceptor agonists, which readily penetrate the blood-brain barrier. They potentiate the locomotor activity that is induced by apomorphine (AP) in reserpinized mice, an effect that has been suggested to result from activation of central -receptors. This effect is selectively blocked by the preferential ₁-antagonist phenoxybenzamine, but not by drugs that block other types of receptors. The effect is also produced by the centrally administered ₁-agonists phenylephrine and methoxamine, but not by various types of standard CNS stimulants. When administered in high doses, some of the aminotetralin compounds induce locomotor activity in reserpinized mice without AP, an effect also found with high doses of centrally administered phenylephrine and methoxamine. This effect is blocked by a series of drugs at doses that correspond to their ₁-antagonist potencies.     

PPAR modulators and PPAR pan agonists for metabolic diseases: the next generation of drugs targeting peroxisome proliferator-activated receptors?

The Peroxisome Proliferator-Activated Receptors-PPAR alpha, PPAR gamma, and PPAR delta--are members of the nuclear receptor gene family that have emerged as therapeutic targets for the development of drugs to treat human metabolic diseases. The discovery of high affinity, subtype-selective agonists for each of the three PPAR subtypes has allowed elucidation of the pharmacology of these receptors and development of first-generation therapeutic agents for the treatment of diabetes and dyslipidemia. However, despite proven therapeutic benefits of selective PPAR agonists, safety concerns and dose-limiting side effects have been observed, and a number of late-stage development failures have been reported. Scientists have continued to explore ligand-based activation of PPARs in hopes of developing safer and more effective drugs. This review highlights recent efforts on two newer approaches, the simultaneous activation of all three PPAR receptors with a single ligand (PPAR pan agonists) and the selective modulation of a single PPAR receptor in a cell or tissue specific manner (selective PPAR modulator or SPPARM) in order to induce a subset of target genes and affect a restricted number of metabolic pathways.     

Pharmacophore identification and validation for human nAChR α7 agonists

Human nAChR α7 is the potential target for schizophrenia cognitive disorders, and it is meaningful to develop selective human nAChR α7 agonists for the clinical treatment of the disease. Because the crystal structure of α7 receptor has not been resolved, ligand-based drug design strategy was took in this work. A 3D QSAR pharmacophore model was built by HypoGen method, and its quality was evaluated by cost function. Furthermore, the pharmacophore model was validated with activity prediction of test set and was cross-validated based on Fisher’s Randomization Method. By Enrichment Factor and AU-ROC analysis, the final pharmacophore, which is consisted of one HBA, two Hydrophobic and one PosIonizable, was selected and it fitted well with the docking result of α7 homology model and the ligand. The pharmacophore is expected for the following virtual screening and lead optimization of human nAChR α7 agonists, which is important for the development and discovery of novel antipsychotics.     

ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD?

There has been a real interest recently in developing once-daily beta(2)-adrenoceptor agonists (ultra-long-acting beta(2)-adrenoceptor agonists [ultra-LABAs]) for treating asthma and chronic obstructive pulmonary disease (COPD) in an attempt to simplify their management, although an increasing amount of convincing data show an association of LABAs with a rise in asthma-related deaths and life-threatening experiences. This paper reviews the effects of different ultra-LABAs that are at varying stages of development. Arformoterol, carmoterol, indacaterol and GSK-159797 are ultra-LABAs that are likely to be introduced into the market before 2010. It is plausible that once-daily dose administration of an LABA will lead to increased convenience for patients, which may also lead to enhancement of adherence, and may have advantages leading to improved overall clinical outcomes in patients with asthma and COPD.     

α-Adrenergic and 5-HT2-serotonergic effects of some β-phenylethylamines on isolated rat thoracic aorta

• 1.1. 2C-H [2-(2,5-dimethoxyphenyl)ethylamine] (pD₂ = 6.74), TMPEA [2-(2,4,5-trimethoxyphenyl)ethylamine] (pD₂ = 5.83), 2C-D [2-(2,5-dimethoxy-4-methylphenyl)ethylamine] (pD₂ = 5.06), homoveratrylamine [DMPEA, 2-(4,5-dimethoxyphenyl)ethylamine] (pD₂ = 4.46) and homopiperonylamine [MDPEA, 2-(3,4-methylenedioxyphenyl)ethylamine] (pD₂ = 4.19), elicit concentration-dependent contraction of the isolated rat thoracic aorta.
• 2.2. At 9.9 × 10⁻⁶ M, 2C-N [2-(2,5-dimethoxy-4-nitrophenyl)ethylamine] behaves as a competitive antagonist to serotonin in this preparation.
• 3.3. Considering previous results with the structurally related 2C-B [2-(4-bromo-2,5-dimethoxyphenyl)ethylamine], weak or partial agonistic activity or antagonism of aortic contraction appears to be related to psychedelic properties reported in humans for phenylethylamines.

     

Long-acting β2 agonists in asthma and allergic rhinitis

Background: Long-acting β₂ agonists (LABAs) are effective second-line bronchodilator controller agents in asthma, although they may also increase the risk of hospitalization and asthma-related death in certain situations. Despite the interesting findings obtained with short-acting β₂ agonists (SABAs), negative studies are available with LABAs in the treatment of allergic rhinitis. This is quite surprising given that there is now clear documentation of the link between asthma and allergic rhinitis. Objective: The aim of this review is to examine the role of β₂ agonists in patients with asthma who also suffer from allergic rhinitis and to try to explain the differences observed between SABAs and LABAs in rhinitis. Methods: SCOPUS, GOOGLE SCHOLAR and MEDLINE were searched for abstracts and papers; the search was completed in March 2008. No restriction was placed on language. Conclusion: The intriguing united airway concept led to the hypothesis that common therapies may influence both and asthma and allergic rhinitis. Consequently, better designed studies with LABAs in allergic rhinitis are now mandatory. In particular, further studies are necessary to investigate clinically relevant anti-inflammatory synergy between inhaled corticosteroids and LABAs in upper airways. It will also be interesting to assess whether ultra-LABAs (once-daily LABAs) are active in allergic rhinitis, although the information we have seems to exclude a role for these agents.     

Long-acting β2 agonists

Two applications claim very closely related arylsulfonamide β₂-agonists. The basic generic claim is the same in both cases with subsidiary claims covering different permutations of the same Markush structure. The claimed compounds are potent β₂-agonists whose structures suggest that they would have a long duration of action. These applications represent part of what is now a significant chemical programme at Pfizer.     

Currently used and investigational drugs for Cushing´s disease

Introduction: Cushing’s disease (CD) is caused by a corticotroph adenoma of the pituitary gland that secretes excess adrenocorticotropic hormone (ACTH) causing increased morbidity and mortality. Surgery is the treatment of choice, but is not always successful. Alternatives include radiotherapy, adrenal surgery, and pharmaceutical therapy. The latter is increasingly gaining momentum due to the recent development of compounds that reduce hypercortisolaemia or its symptoms, acting through different mechanisms.

Areas covered: In this article, the authors provide a complete overview of the treatment options for Cushing´s disease, including adrenal-directed, tumor-targeted, and peripheral therapies that are currently used or in development, and discuss their potential advantages and limitations.

Expert opinion: Considering the lack of long-term remission in up to half of the patients after surgery, and the delayed response to radiotherapy along with potential side effects, there is a strong need for an effective pharmaceutical treatment. Pasireotide, mifepristone, ketoconazole and metyrapone have been approved by regulatory authorities but their use remains limited due to considerable costs and side effects. Research in this field has focused recently on the improvement of pre-existing drugs and the development of safe new ones. However, few approaches aim at targeting the source of the disease, the ACTH-secreting adenoma.     

Looking for agonists of β2 adrenergic receptor from Fuzi and Chuanwu by virtual screening and dual-luciferase reporter assay

More and more studies demonstrated that β₂ adrenergic receptor (β₂-AR) plays a crucial role for the treatment of heart failure. Chuanwu and Fuzi have been used over thousands of years in China for the treatment of heart failure. Considering the effects of these herbs are very similar to β₂-AR agonists, we presume whether β₂-AR agonists can be found from Fuzi and Chuanwu. Fuzi and Chuanwu decoction were used to receive the luciferase reporter activity assay to verify the hypothesis, and the result is positive and encouraging. For it is very difficult to get all of the monomer compounds of Fuzi and Chuanwu, virtual screening was used to find potential β₂-AR agonists and a cell-based β₂-AR agonist functional evaluation model, combined with a luciferase reporter assay system, was used to confirm the final result. In this research, 45 compounds were identified as β₂-AR agonists, and four compounds were verified and the rest need further experiment.     

Evidence for thromboxane receptor mediated contraction of guinea-pig and human airways in vitro by prostaglandin (PG) D2, 9α,11β-PGF2 and PGF2α

Summary The rank orders of potency of prostaglandin D₂, prostaglandin F₂, 9,11-prostaglandin F₂ and the stable thromboxane A₂ mimetics U-46619 and ONO-11113 were determined in guinea-pig trachea and human bronchus in vitro. In both tissues the thromboxane mimetics were markedly more potent than the other prostanoids with EC₅₀ values in the nanomolar range. The prostanoid antagonists BW-245C, EP-092 and GR-32191 attenuated the contractile responses to all of the prostanoid agonists and TXA₂ mimetics tested in guinea-pig tracheal spirals, although agonist selectivity was seen. Contractile responses to methacholine in the guinea-pig trachea were unaffected by any of the antagonists employed. BW-245C antagonised the effects of all prostanoid agonists tested in human bronchial spirals, the pA₂ values obtained were similar to those seen in the guinea-pig trachea when U-46619 and 9,11-PGF₂ were employed as the agonists. However, significant differences were found between the two tissues when PGD₂ and PGF₂. were tested against BW245C. EP-092 produced pA₂ values against prostanoid agonists in the human bronchus similar to those seen in the guinea-pig trachea, as did GR-32191. It is concluded that whilst the contractile responses of guinea-pig and human airways smooth muscle to prostaglandin D₂, and the other prostanoids are mediated predominantly via thromboxane (TP) receptors, it can be inferred that other receptor populations may contribute to the contractile response. The presence of these minor subpopulations may account for the agonist selectivity seen both within and between tissues from different species. Send offprint requests to: R. L. Featherstone at the above address     

PPAR-β/δ agonists for Type 2 diabetes and dyslipidemia: an adopted orphan still looking for a home

Background: The identification of small molecule agonists for the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR-β/δ, NR1C2) has enabled the characterization of this receptor's functions in preclinical models. Subsequently, a number of small molecule agonists of PPAR-β/δ have been progressed into clinical trials. Objective: This review will examine the major preclinical findings that underpin the hypothesis that PPAR-β/δ agonists may be beneficial in treating dyslipidemia and Type 2 diabetes, as well as emerging clinical data with a variety of PPAR-β/δ agonists. Methods: The literature concerning preclinical experiments that combine in vivo and in vitro mechanistic studies are reviewed and compared with the results of the early clinical trials. Conclusions: Thus far, the activities of the agonists seen in the clinic are broadly similar to those seen in preclinical models. However, it is still not known if PPAR-β/δ agonists will truly be differentiated enough from current treatments to justify their use in treating dyslipidemia or Type 2 diabetes. Major challenges for the development of PPAR-β/δ agonists exist and the path forward is as yet undefined.     

Characterization of the self-association of human interferon-α2b, albinterferon-α2b, and pegasys

The self-association of human interferon-α2b (hIFN-α2b), albinterferon-α2b (a recombinant protein with human serum albumin and hIFN-α2b peptides fused together in a single polypeptide chain), and Pegasys (PEGylated hIFN-α2a) was characterized by analytical ultracentrifugation analyses. By examining the apparent sedimentation coefficient distribution profiles of each protein at different concentrations, it was concluded that the above three proteins are self-associating in albinterferon-α2b formulation buffer. By model fitting of sedimentation data using SEDANAL software, the stoichiometry and equilibrium constants of the self-association of these proteins were characterized. The self-association of hIFN-α2b results in the formation of stable dimers, fast-reversible tetramers, octamers, and hexadecamers. In contrast, although both albinterferon-α2b and Pegasys are self-associated, their self-association stoichiometries are significantly different from that of hIFN-α2b. The self-association of albinterferon-α2b results in the formation of reversible dimers and trimers, whereas the self-association of Pegasys gives only reversible dimers. The self-association behaviors of hIFN-α2b and albinterferon-α2b involves attractive electrostatic forces, which can be suppressed to a negligible level in low pH (pH 4.0-4.5) and high salt concentration (400 mM NaCl) buffer, allowing quantification of their size variant contents by sedimentation velocity analysis.