1989 — 2007 |
Rice, Kenner C |
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Design and Synthesis of Drugs Acting On Central and Peripheral Tissues @ Diabetes, Digestive, Kidney Diseases
The abuse of cocaine is widely recognized to be an extremely serious health and social problem of epidemic proportions for which there is no effective treatment. As part of our collaborative studies on the structure and function of the mammalian central nervous system (CNS), we have shown that GBR 12909 is a slowly dissociating, high affinity inhibitor of dopamine uptake. This drug largely blocks cocaine elevation of extracellular dopamine in the nucleus accumbens of rats as measured by in vivo microdialysis. We also showed that GBR 12909 prevents cocaine self-administration in rhesus monkeys trained to self-administer cocaine with no effect on normal behavior as measured by food maintained responding. We have now utilized positron emission tomography (PET) to validate and extend these studies by showing that doses of GBR 12909 which greatly reduce cocaine self-administration in monkeys produce high dose related occupation of dopamine transporters. These studies strongly suggest that GBR 12909 produces suppression of cocaine self- administration by occupancy of the dopamine receptor and that this drug and/or its congeners may be of substantial value in the treatment and prevention of human cocaine abuse. In other studies, we continued the design, chemical synthesis and evaluation of delta opioid receptor agonists and antagonists as potential analgesics and drugs for the treatment and prevention of cocaine and narcotic abuse. One of these drugs is SNC 80, which we have found to be a highly selective delta opioid receptor agonist. We have now shown that it has no effect in several measures of immune function in the rat while elevating others suggesting that delta opioid ligands may be useful in pain management in normal and immunocompromised individuals. Our chemical synthesis studies have resulted in the following advances: Novel methodology for the N-deprotection and O- demethylation of opium alkaloids and derivatives; synthesis of 3- substituted-3-deoxynaltrindole derivatives; a novel synthesis of thebaine from codeine; and a direct and simple conversion of codeine to thebainone-A and dihydrothebainone. Finally, we have developed novel drugs as tools for study of corticotropin releasing hormone (CRH) receptors including potential agents for PET and single photon emission computed tomography (SPECT) imaging of CRH receptors in living animals and humans.
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2008 — 2016 |
Rice, Kenner |
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Medicinal Chemistry in the Study of Alcohol Abuse @ National Institute On Drug Abuse
Genetic and early environmental factors interact to influence ethanol's motivational effects. To explore these issues, a reciprocal cross-fostering paradigm was applied to Fischer and Lewis rats. The adult female offspring received vehicle or the kappa opioid antagonist nor-BNI (1 mg/kg) followed by assessments of conditioned taste aversion (CTA), blood alcohol concentrations (BACs) and hypothermia induced by 1.25 g/kg intraperitoneal ethanol. CTA acquisition in the in-fostered Fischer and Lewis animals did not differ;however, the Fischer maternal environment produced stronger acquisition in the cross-fostered Lewis rats versus their in-fostered counterparts. CTAs in the Fischer rats were not affected by cross-fostering. In extinction, the in-fostered Lewis animals displayed stronger aversions than the Fischer groups on two trials (of 12) whereas the cross-fostered Lewis differed from the Fischer groups on nine trials. Despite these CTA effects, Lewis rats exhibited higher BACs and stronger hypothermic responses than Fischer with no cross-fostering effects in either strain. No phenotypes were affected by nor-BNI. These data extend previous findings dissociating the aversive and peripheral physiological effects of ethanol in female Fischer and Lewis rats, and highlight the importance of genetic and early environmental factors in shaping subsequent responses to alcohol's motivational effects in adulthood. Our studies in the role of stress in alcohol abuse have continued. We and others have shown that stress can play an important role in promoting alcohol self-administration and relapse to drug abuse. The corticotropin releasing hormone receptor (CRHR1) plays a central role in initiation of the response to stress. Our studies suggest that CRHR1 antagonists such as antalarmin may be useful in the treatment of human alcohol dependence and relapse to other drugs of abuse, and that optimal treatment may vary between different subtypes of patients. We also tested the hypothesis that sigma receptors modulate ethanol reinforcement and contribute to excessive ethanol intake. We utilized the potent, selective sigma-1 receptor antagonist BD-1063 developed earlier in our laboratory in a number of rat models of alcohol self-administration. Our results also suggest that sigma receptor may contribute to innate or ethanol-induced increases in susceptibility to self-administer high ethanol levels, identifying a potential neuroadaptive mechanism contributing to excessive drinking and a therapeutic target for alcohol abuse and dependence.
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0.915 |
2008 — 2018 |
Rice, Kenner |
Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Medicinal Chemistry of Drugs Acting On Biogenic Amine Receptors @ National Institute On Drug Abuse
The abuse of psychomotor stimulants such as cocaine and methamphetamine is a continuing and very serious problem worldwide. In our program to synthesize and evaluate a number of 5-HT agonists and their antagonists, we earlier developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907 that is providing multigram amounts of this critical research tool. We have also studied the discriminative stimulus effects of MDL100,907 and several other drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. Relapse to cocaine self-administration is a major obstacle to overcome in the successful treatment of human cocaine addicts. Such relapse can be triggered by impulsivity or cue reactivity. It is well established that the dopamine and serotonin (5-HT) receptor systems are involved in the regulation of impulsive behavior in animals and humans and prior studies have implicated the 5HT2A receptor subtype. We used the 5HT2A receptor antagonist MDL100907 to examine the question of whether this drug would suppress cocaine-induced impulsivity in two established rat models of impulsive behavior. MDL100907 attenuated impulsivity in the differential reinforcement of low rate (DRL) task and the one-choice serial reaction time (1-CSRT) task. Our results suggest that 5-HT2A receptor antagonists will be useful in further study of cocaine-induced impulsivity and may be may be therapeutically useful in the treatment of cocaine abuse and other impulse-control disorders. Preclinical studies have now shown that impulsivity and cocaine seeking behavior can be suppressed by relatively large doses of either a selective 5-HT2A antagonist or a selective 5HT2C agonist. We evaluated the possibility that low doses (to avoid side effects) of both a 5-HT2A antagonist MDL100907 and a 5HT2C agonist WAY163909 be effective and offer advantages over single drug treatment in preventing relapse. Our results showed that low doses of both drugs in combination was effective when the same doses separately had no effect. The drug mixture suppressed cocaine-induced inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. This is an important finding that suggests that a single drug showing both profiles in the optimum ratio could constitute a valuable medication for the prevention of cocaine relapse.
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0.915 |
2008 — 2018 |
Rice, Kenner |
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Medicinal Chemistry of Drugs Acting On Central and Peripheral Opioid Receptors @ National Institute On Drug Abuse
We have continued our studies of the opioid receptor-endorphin system from medicinal chemical and pharmacological directions. This system consists of saturable, enantioselective, high affinity mu, delta and kappa opioid receptor types and their subtypes located in anatomically well defined areas of the mammalian CNS with the numerous endogenous opioid peptides (endorphins) which subserve these receptors. These results present many opportunities for research highly relevant to drug abuse and for the development of new medications that act on these receptors. The opioid receptor endorphin system mediates the analgesic, euphoric and addictive effects of narcotic drugs and contributes to regulation of numerous physiologic and behavioral functions in its normal state including regulation of dopamine (DA) levels in the nucleus accumbens (NAC) and expression of the effects of alcohol and cocaine. This system is dysregulated by the abuse of heroin and prescription narcotics resulting in tolerance and dependence. Recent pharmacologic advances have shown that moderately selective delta opioid antagonists suppress (a) cocaine seeking behavior, (b) heroin self-administration and (c) the development of tolerance and dependence to the mu agonist morphine. The former two observations strongly indicate that highly selective delta receptor antagonists might be valuable medications for the treatment and prevention of human cocaine and narcotic abuse and perhaps other undesirable reinforcing behaviors. The latter observation suggests that a drug showing a mu agonist-delta antagonist profile might produce strong analgesia without producing tolerance and dependence thus allowing continuous treatment of chronic pain. The exploitation of these and other similarly intriguing observations now requires novel, exquisitely selective, nonpeptide ligands as research tools and potential medications. These new tools will enable the study of many questions of fundamental importance concerning the function of mu, delta and kappa opioid receptor subtypes and how drugs interact with their receptors to elicit these functions. We have continued to design, synthesize and evaluate novel drugs for this purpose during the reporting period. The 5-phenylmorphans are a particularly interesting class of opioid receptor agonists that were originated by Everette May at NIH in 1955. We earlier identified a mu agonist-delta antagonist and a delta inverse agonist in this series. We have now identified a morphine-like mu agonist and also a mu antagonist in a series of conformationally restrained 5-phenylmorphans. The diverse profiles obtained in this series illustrate the importance of subtle changes on the carbon-nitrogen skeleton and careful attention to stereochemical detail and provide important leads toward novel pain medications with reduced side effects and further understanding of drug-receptor interactions. We are now addressing the major unanswered question of the optimum degree of mu agonism and either delta agonism or antagonism in a single compound for the ideal strong analgesic. We are presently pursuing this question in primate studies in collaboration with Steve Negus at the Medical College of Virginia who is utilizing our delta agonist SNC80 and other related compounds in combination with strong mu agonists. We have also identified systemically active drugs in the unbridged phenylmorphan series that show mu agonism and delta antagonist activity in the same compound. We are presently extending this work in (a) oxide-bridged and (b) nonbridged 5-phenylmorphans, and (c) other appropriate partial structures. Collaborative computer assisted molecular modeling and ab initio quantum mechanical methods are being employed in the design of these compounds. These novel drugs are being studied in the appropriate in vitro binding assays in native and cloned systems, smooth muscle assays, in vivo assays in small animals, and self-administration and other studies in rhesus monkeys. We recently found that 20R-epoxyresibufogenin formate (20R-ERBF) is systemically available and orally effective in blocking chronic pain in animal models of bone cancer pain and pancreatitis by antagonizing interleukin 6 (IL-6). We characterized it as a reversible IL-6 receptor antagonist with femtomolar affinity that acts through peripheral mechanisms. The only presently available human therapy for IL-6-related disorders is tocilizumab, an expensive (15-20K/year/patient), monoclonal antibody against the IL-6 receptor itself. Nevertheless, the clinical effectiveness of tocilizumab validates the mechanism of suppressing IL-6 function and the notion that a small molecule antagonist of the IL-6 should be a much more advantageous treatment for inflammatory pain than an antibody against the IL-6 receptor. In addition, it is well known that excessive levels of IL-6 play a role in the pathogenesis of a number of disorders including rheumatoid arthritis, Crohn's disease, multiple sclerosis, Castleman's disease, and certain types of leukemias and tumors, as well as depression, cardiomyopathy, and atherosclerotic disease, osteoporosis, diabetic neuropathy. A clinically acceptable, small molecule IL-6 antagonist should also be useful in treating these disorders and offer great advantages over tocilizumab therapy. Such treatment could offer distinct advantages to the use of narcotics that produce dependence, tolerance and in some cases life-threatening constipation. Combination of the IL-6 antagonist with narcotic therapy for severe pain should lower the dose of narcotic required and thus reduce narcotic-mediated side effects. In summary, we have identified 20R-ERBF (7) as an orally effective IL-6 receptor antagonist that blocks chronic pain in two animals models and provides an important lead to novel nonnarcotic agents for the treatment of pain. This compound or a derivative may also offer great advantages over an expensive biological treatment to block the actions of IL-6 and provide a novel therapeutic for a number of disease states.
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0.915 |
2008 — 2018 |
Rice, Kenner |
Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Medicinal Chemistry of Drugs Acting On Crh Receptors @ National Institute On Drug Abuse
The stress system is well known to play an important role in relapse to drug abuse and excessive eating and is largely controlled by corticotropin releasing hormone receptors (CRHR) and their endogenous ligands. Recent work has shown that stress and corticotropin-releasing hormone (CRH) are involved in the pathogenesis of Alzheimer's disease (AD), but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models. We have examined the question of whether antagonism of the type-1 corticotropin-releasing hormone receptor (CRHR1) could be used as a disease-modifying treatment for AD, we used a preclinical prevention paradigm and treated 30-day-old AD transgenic mice with the small-molecule, CRHR1-selective antagonist, R121919, (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylaminopyrazolo1,5-apyrimidine) for 5 months, and examined AD pathologic and behavioral end points. We found that R121919 significantly prevented the onset of cognitive impairment in female mice and reduced cellular and synaptic deficits and beta amyloid and C-terminal fragment- levels in both genders. We observed no tolerability or toxicity issues in mice treated with R121919. We conclude that CRHR1 antagonism may present a viable disease-modifying therapy for AD, and that appropriate CRHR1 antagonists should be considered for human studies.
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0.915 |
2008 — 2018 |
Rice, Kenner |
Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Medicinal Chemistry of Drugs Acting On Toll-Like Receptors @ National Institute On Drug Abuse
We recently introduced the concept of toll-like receptor (TLR)-mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. We demonstrated that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (-)-isomer opioid antagonist (+)-naloxone has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia) and unwanted (tolerance, dependence, and reward) actions of opioids, thereby improving the safety and efficacy of their use. Our finding with (+)-naloxone is of potential clinical relevance. This is because (+)-naloxone is an antagonist that is inactive at the (-)-opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)-opioid antagonists such as (+)-naloxone may be useful clinically to suppress glial activation, yet (-)-opioid agonists suppress pain.
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0.915 |
2008 — 2016 |
Rice, Kenner |
Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Medicinal Chemistry of Hallucinogenic Drugs @ National Institute On Drug Abuse
The abuse of psychomotor stimulants such as cocaine and methamphetamine is a continuing and very serious problem worldwide for which there is no accepted medication. Numerous lines of investigation indicate that elevation of dopamine (DA) in the nucleus accumbens (NAC) is largely responsible for the reinforcing (rewarding) effects of many classes of drugs including cocaine and methamphetamine. Although the precise mechanism of DA elevation in the NAC differs among drug classes, medications that suppress or deplete such elevation of DA may thus be useful in the treatment and prevention of diverse, destructive self-administration behaviors including excessive eating. We have pursued the chemical synthesis and identification of biogenic amine agonists and their antagonists as research tools and potential medications. In one example, we developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907 that is enabling numerous studies requiring this critical research tool. We have also studied the discriminative stimulus effects of MDL100,907 and several other drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. In 1992, we introduced the selective sigma-1 receptor (Sig-1R) antagonist BD-1063 that has become a valuable research tool in the study of the Sig1R. Based on results from a number of laboratories, the Sig-1R has been proposed as a novel therapeutic target for drug and alcohol addiction. Earlier, we showed Sig-1R agonists facilitate the reinforcing effects of ethanol and induce binge-like drinking, while Sig-1R antagonists block excessive drinking in genetic and environmental models of alcoholism. Even though significant progress has been made in understanding the function of Sig-1R in alcohol reinforcement, its role in the early and late stage of alcohol addiction remains unclear. We have now shown that administration of BD-1063 dramatically reduced the acquisition of alcohol drinking behavior as well as the preference for alcohol in genetically selected TSRI Sardinian alcohol preferring (Scr:sP) rats. We observed that the treatment had no effect on total fluid intake, food intake or body weight gain, indicating selectivity of action. Furthermore, BD-1063 dose-dependently decreased alcohol-seeking behavior in rats trained under a second-order schedule of reinforcement, in which responding is maintained by contingent presentation of a conditioned reinforcer. Finally, an innate elevation in Sig-1R protein levels was found in the nucleus accumbens of alcohol-preferring Scr:sP rats, compared to outbred Wistar rats, alteration which was normalized by chronic, voluntary alcohol drinking. Taken together these findings demonstrate that Sig-1R blockade reduces the propensity to both acquire alcohol drinking and to seek alcohol, and point to the nucleus accumbens as a potential key region for the effects observed. Our data suggest that Sig-1R antagonists may have therapeutic potential in multiple stages of alcohol addiction.
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