Use Of Partial Agonists Research Articles

Design of κ-Opioid Receptor Agonists for the Development of Potential Treatments of Pain with Reduced Side Effects.

The κ-opioid receptor (KOR) has recently emerged as an alternative therapeutic target for the development of pain medications, without deleterious side effects associated with the μ-opioid receptor (MOR). However, modulation of KOR is currently under investigation for the treatment of depression, mood disorders, psychiatric comorbidity, and specific drug addictions. However, KOR agonists also trigger adverse effects including sedation, dysphoria, and hallucinations. In this respect, there is currently much debate on alternative paradigms. Recent effort has been devoted in search of biased ligands capable of selectively activating favorable signaling over signaling associated with unwanted side effects. On the other hand, the use of partial agonists is expected to allow the analgesia to be produced at dosages lower than those required to produce the adverse effects. More empirically, the unwanted central effects can be also avoided by using peripherally restricted agonists. In this review, we discuss the more recent trends in the design of KOR-selective, biased or partial, and finally, peripherally acting agonists. Special emphasis is given on the discussion of the most recent approaches for controlling functional selectivity of KOR-specific ligands.

制止学習アプローチに基づいたエクスポージャーの研究動向

The purpose of this study was to conduct a systematic review of the literature on exposure therapy based on an inhibitory learning approach and to comprehensively summarize the accumulation of studies on this approach and its effectiveness. A literature search was conducted using PubMed, PsycINFO, and Web of Science. A screening and eligibility assessment identified 59 articles on exposure therapy based on the inhibitory learning approach. The literature was categorized according to the inhibitory learning approach’s specific strategies, and the intervention’s effects were reviewed. As a result of the overview, it became clear that there was an insufficient number of studies for each study, except for those pertaining to the use of partial agonists of NMDA receptors. Furthermore, although 33 of the 59 studies showed intervention effects, the breakdown of the studies was skewed. Therefore, it is thought that the inhibitory learning approach is not adequately effective, and further research data and research methods should be devised in the future.

Abstract 4856: Selective human estrogen receptor partial agonist (ShERPAs) for treatment of tamoxifen-resistant ER+ breast cancer

Abstract Estrogen receptor positive (ER+) breast cancer represents a significant cause of death among women in the US, which is exacerbated by resistance to 1st line endocrine therapies, notably tamoxifen, which occurs in 50% of patients. Estrogen fuels growth of endocrine-dependent cancers and yet estradiol (E2) and ERá agonist, diethylstilbestrol, were used successfully in the clinic in greats cancer therapy in the 20th century. The side effects associated with these treatments are considered unacceptable, spurring the pursuit of safer, alternative therapeutic agents and the model systems to develop and optimize these agents. Three breast cancer cell lines that demonstrate resistance to tamoxifen and endocrine independence in 2D (MCF-7:5C), or 3D (T-47D:PKCá and T-47D:TAM1) cell cultures; and comparison to the parent endocrine-dependent cell lines provides a set of model systems able to test the hypothesis that a selective estrogen mimic (SEM) will provide a safe, therapeutic approach to ER+ endocrine-independent breast cancer overexpressing the PKCá biomarker. A partial agonist at ERá was selected as such a therapeutic approach: The use of partial agonists will allow us to retain the beneficial properties of E2, while attenuating the unwanted side effects. Selective human Estrogen Receptor Partial Agonists (ShERPAs) were designed, synthesized, and validated, using a combination of time-resolved FRET (TR-FRET) on ERá/SRC3 recruitment, isolated ERá affinity, and cell-based assays. ShERPAs were identified containing novel structures derived from the selective estrogen receptor modulators (SERMs) bazedoxifene and raloxifene, and their scaffolds, 3-methylindole and benzothiophene, respectively. Examples with favorable pharmacokinetic properties were validated in xenograft models of tamoxifen-resistant breast cancer. Citation Format: Loruhama M. Delgado-Rivera. Selective human estrogen receptor partial agonist (ShERPAs) for treatment of tamoxifen-resistant ER+ breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4856.

P.2.020 The novel antipsychotic brexpiprazole partly reverses a disruption of thalamocortical function induced by phencyclidine

Dopaminergic dysfunction is thought to be central to schizophrenia symptomatology. Previous meta-analyses of prodopaminergic drugs in schizophrenia have important limitations, and also did not include dopamine D2/D3 partial agonists. We investigated the effect of medications which increase dopamine signalling on schizophrenia symptoms by meta-analysing double-blind, placebo-controlled RCTs. 59 RCTs were included: 29 of prodopaminergic treatments, 30 of partial agonists. Partial agonists were significantly superior to placebo against positive (SMD=−0.33,p = 1.2 ×10-17), negative (SMD=−0.29,p = 2.2 × 10-31) and total symptoms (SMD =−0.39,p = 1.7 × 10-30) in schizophrenia. There were no significant differences between pooled pro-dopaminergic drugs and placebo in any symptom domain. In subgroup analysis of five studies where patients were selected for negative symptom severity, ar/modafinil was superior to placebo against negative symptoms (SMD=−0.34,p = 0.037). These data favour the clinical use of partial agonists for negative symptoms in schizophrenia, with clinically meaningful effect sizes. Our findings also suggest a benefit for ar/modafinil in patients with predominant negative symptoms. Future trials of other prodopaminergic therapies and dopamine partial agonists in patients with predominant negative symptoms are warranted.

Role of nicotine receptor partial agonists in tobacco cessation.

One in three adults in India uses tobacco, a highly addictive substance in one or other form. In addition to prevention of tobacco use, offering evidence-based cessation services to dependent tobacco users constitutes an important approach in addressing this serious public health problem. A combination of behavioral methods and pharmacotherapy has shown the most optimal results in tobacco dependence treatment. Among currently available pharmacological agents, drugs that preferentially act on the α4 β2-nicotinic acetyl choline receptor like varenicline and cytisine appear to have relatively better cessation outcomes. These drugs are in general well tolerated and have minimal drug interactions. The odds of quitting tobacco use are at the very least doubled with the use of partial agonists compared with placebo and the outcomes are also superior when compared to nicotine replacement therapy and bupropion. The poor availability of partial agonists and specifically the cost of varenicline, as well as the lack of safety data for cytisine has limited their use world over, particularly in developing countries. Evidence for the benefit of partial agonists is more robust for smoking rather than smokeless forms of tobacco. Although more studies are needed to demonstrate their effectiveness in different populations of tobacco users, present literature supports the use of partial agonists in addition to behavioral methods for optimal outcome in tobacco dependence.

Partial agonists and suicide: the role of the mental health nurse

This paper explores the theoretical risks associated with the increase of suicide in people with schizophrenia treated with partial agonists (dopamine system stabilizers). The paper discusses what we think may be happening in the brains of people with schizophrenia which contributes to their difficulties, how antipsychotic medication can ease these difficulties, and the pharmacological theory as to why an increased risk of suicide may occur with the use of partial agonists. Finally, the core nursing interventions to minimize the potential risks of suicide when caring for people who are prescribed partial agonists are described. Language: en

The place of partial agonism in psychiatry: recent developments

Drugs used to treat psychiatric disorders, although effective, are often restricted by adverse events. The use of partial agonists for treating hypertension was found to limit some of the side-effects in some patients. This led to the investigation of partial agonists as a treatment modality in psychiatric disorders. Partial agonists have a lower intrinsic efficacy than full agonists leading to reduced maximum response. They can act as antagonists by competing for receptor binding with full agonists. The level of activity depends on the level of endogenous receptor activity. Buprenorphine, a partial agonist at the mu-opioid receptor, is used to treat patients with addiction and decreases the symptoms of withdrawal and risks of overdose and intoxication. The anxiolytic buspirone shows partial agonism at 5-HT(1A) receptors, and this seems to provide anxioselective effects, without inducing extrapyramidal side-effects, convulsions, tolerance or withdrawal reactions. In schizophrenia, partial dopamine agonism results in antagonistic effects at sites activated by high concentrations of dopamine and agonistic effects at sites activated by low concentrations of dopamine. This stabilizes the dopamine system to effect antipsychotic action without inducing adverse motor or hormonal events. Aripiprazole is the first 'dopamine system stabilizer', and the data are promising, with efficacy at least equivalent to that with current atypical antipsychotics but fewer of the troublesome side-effects. Partial agonists seem to provide a way to fine-tune the treatment of psychiatric disorders by maximizing the treatment effect while minimizing undesirable adverse events.

Aripiprazole Attenuates the Discriminative-Stimulus and Subject-Rated Effects of D-Amphetamine in Humans

The results of animal research suggest that the use of partial agonists at dopamine (DA) D2 receptors may be an effective strategy for the treatment of stimulant dependence. Aripiprazole is an atypical antipsychotic that has partial agonist activity at D2 receptors. In this experiment, seven human participants with a history of nontherapeutic stimulant use learned to discriminate 15 mg oral D-amphetamine. After acquiring the discrimination (ie > or =80% correct responding on four consecutive sessions), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with aripiprazole (0 and 20 mg), were assessed. D-Amphetamine alone functioned as a discriminative stimulus, produced prototypical subject-rated drug effects (eg increased ratings of Active, Alert, Energetic) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion D-amphetamine-appropriate responding or produce subject-rated effects, but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of D-amphetamine, as well as some of the subject-rated drug effects. These data are consistent with previous preclinical findings and suggest that DA partial agonists deserve further evaluation as potential pharmacotherapies in the management of stimulant dependence. Future studies should investigate the ability of aripiprazole or related compounds to attenuate the behavioral effects of stimulants associated with a greater degree of dependence, such as methamphetamine or cocaine, in dependent individuals.

Adenosine A(1) receptor: analysis of the potential therapeutic effects obtained by its activation in the central nervous system.

Adenosine modulates several physiological functions in the CNS and in peripheral tissues via membrane receptors which have been classified into four adenosine subtypes. A(1) activation produces neuronal depression: this inhibition allows A(1) agonists to produce ischemic tolerance and protection in neuronal tissue. In order to selectively reproduce these effects, several A(1) selective ligands have been synthesised and evaluated to understand how they interact with the adenosine A(1) receptor. The investigation methods include SAR studies using native and chemically modified A(1) receptors, molecular cloning of native and mutant adenosine A(1) receptors, molecular modeling and thermodynamic analysis of drug-receptor interaction. Despite the great quantity of information available on the adenosine A(1) receptor, no A(1) agonist has so far entered in clinical use against brain diseases in view of the side effects; moreover selective A(1) agonists appear to be poorly adsorbed into the brain and can be quickly degraded in vivo or in the whole blood. In an attempt to overcome these problems studies have been undertaken dealing with the use of partial agonists to inhibit side-effects and the employment of prodrugs to increase stability and diffusion through lipid barriers of A(1) ligands. Other attempts involve either the use of A(1) receptor enhancers as modulators able to locally enhance the action of endogenously produced adenosine, or the encapsulation of A(1)agonists in drug delivery systems targeted to the brain. In this review, these approaches will be described together with the effects of adenosine A(1) receptor ligands and their binding mechanisms on the central nervous system.

A partial agonist of the A(1)-adenosine receptor selectively slows AV conduction in guinea pig hearts.

The use of full agonists of the A(1)-adenosine receptor (A(1)-ADOR) as antiarrhythmic agents is limited by their actions to cause high-grade atrioventricular (AV) block, profound bradycardia, atrial fibrillation, and vasodilation. It may be possible to avoid these undesired actions by use of partial agonists. We determined the effects of CVT-2759, a potential partial agonist of A(1)-ADORs, on guinea pig hearts. CVT-2759 (0.1-100 microM) increased the S-H interval of the isolated heart from 45 +/- 1 to 60 +/- 3 ms (P < 0. 01) with a half-maximal effect at 3.1 microM. CVT-2759 did not cause second-degree AV block. CVT-2759 significantly attenuated the actions of the full agonists N(6)-cyclopentyladenosine and adenosine. CVT-2759 caused a moderate slowing of atrial rate by </=13% and did not shorten the durations of either the atrial or the ventricular monophasic action potential. Coronary conductance was increased by CVT-2759 only at concentrations >10 microM. In contrast, CVT-2759 was a full agonist to decrease cAMP content of rat adipocytes and Fischer rat thyroid line 5 cells. Results of radioligand binding assays indicated that CVT-2759 stabilized a high-affinity, G protein-coupled state of the A(1)-ADOR in membranes prepared from rat adipocytes but not in membranes prepared from the guinea pig brain. The results suggest that a weak A(1)-ADOR agonist, such as CVT-2759, may be useful to slow AV nodal conduction and thereby ventricular rate without causing AV block, bradycardia, atrial arrhythmias, or vasodilation.

Alternative Agents in Pharmacological Management of Sickle Cell Pain Crisis Complicated by Acute Pancreatitis.

Pain is a prominent presenting complaint in the vaso-occlusive crisis of sickle cell anemia and that of acute pancreatitis. The treatment of pain may extend for hours or days up to weeks for an episode. Treatment by pharmacotherapy often includes opiate/opioid analgesics, nonopiate analgesics and coanalgesics. Repeated acute painful episodes expose the patient to opiate induced effects. This case report describes a treatment option that was developed in order to provide effective analgesia while minimizing the iatrogenic effects produced by commonly used opioids. The use of partial agonists, mixed agonists, nonsteroidal anti-inflammatory agents and coanalgesics can provide objective and subjective analgesia without precipitating drug seeking behaviors or significant iatrogenic effects. Pain management in this clinical setting requires a balanced biopsychosocial approach.

Clinically relevant differences among the opioid analgesics

The mechanism of action of opioids and clinically relevant differences among the opioid analgesics are described. Both endorphins (endogenous morphine-like substances) and exogenous opioids (opium alkaloids and their derivatives) bind to opioid receptors in the human central nervous system to provide analgesia and other effects. Some drugs, such as morphine, are true agonists, i.e., they bind to and activate receptors. Some are partial agonists, binding to part of the receptor and causing effects that are similar to, but perhaps less pronounced than, the effects produced by agonists. Others are antagonist, i.e., they bind to the receptor but do not cause the associated effects. Some drugs, termed agonist-antagonist opioids, act as antagonists at one type of receptor and agonists at another type of receptor. True agonists tend to have relatively straight-line dose-response curves; in other words, their effect increases with increasing doses over a broad dosage range. Partial agonists and agonist-antagonists tend to have ceiling effects; that is, they do not have the broad dosage range of drugs such as morphine, methadone, hydromorphone, and other "strong" opioids. This fact mediates against the use of partial agonists and agonist-antagonists in cancer patients who have chronic pain that may increase as the disease progresses. Three major factors that should be considered when a drug is selected for clinical use are (1) relative affinities for the different opioid receptor types, (2) pharmacokinetic characteristics that influence onset and duration of action, and (3) whether the opioids are strong or weak. For treatment of cancer pain, drugs with long durations of action are preferable.(ABSTRACT TRUNCATED AT 250 WORDS)

The potential antipsychotic activity of the partial dopamine receptor agonist (+) N-0437

The (+) enantiomer of the very potent and selective dopamine D-2 agonist, 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437), displays partial agonistic activity at dopamine D-2 receptors. In this study (+)N-0437 was investigated for its antagonistic activity at postsynaptic DA receptors in four behavioural tests which are commonly used to evaluate potential neuroleptic activity, i.e. d-amphetamine-induced stereotypy, passive avoidance responding, intracranial self-stimulation behaviour, and catalepsy. (+)N-0437 (25–50 μmol/kg) was active in the first three models, but did not cause catalepsy. Haloperidol, which was used as a reference compound for classical DA antagonists, showed clear activity in all four models at low doses (0.5–1.0 μmol/kg). (−)N-0437, a full D-2 agonist, displayed no activity in these behavioural models. These results suggest that (+)N-0437 could be used to examine the hypothesis that the use of partial agonists could provide a new treatment for schizophrenia.

Temperature dependence of β1-adrenoceptor-mediated responses examined by use of partial agonists

The inotropic and chronotropic responses of guinea pig atria, and the relaxation responses of guinea pig intestine, trachea, lung, uterus and vas deferens to catecholamines have been examined at bath temperatures of 38°C and 30°C. Hypothermia resulted in a supersensitivity of cardiac tissues with a decrease in isoprenaline EC 50 and an increase in the maximum response to the partial agonist, salbutamol. Ileum responses to isoprenaline were potentiated at 30°C but no partial agonist could be found on this tissue. Responses of the lung and vas deferens to partial agonists were not affected by temperature, while uterine responses were inhibited by hypothermia. The trachea was supersensitive to isoprenaline at 30°C, however this was not due to a change in β-adrenoceptor sensitivity but an inhibition of COMT. Partial agonist responses of trachea were similar at both temperatures. β-Adrenoceptor supersensitivity was therefore observed only where responses are mediated primarily by β 1-adrenoceptors and supports the concept that β 1- but not β 2-adrenoceptors exhibit hypothermia-induced supersensitivity.