RB101-mediated Protection of Endogenous Opioids: Potential Therapeutic Utility?

The endogenous opioids met- and leu-enkephalin are inactivated by peptidases preventing the activation of opioid receptors. Inhibition of enkephalin-degrading enzymes increases endogenous enkephalin levels and stimulates robust behavioral effects. RB101, an inhibitor of enkephalin-degrading enzymes, produces antinociceptive, antidepressant, and anxiolytic effects in rodents, without typical opioid-related negative side effects. Although enkephalins are not selective endogenous ligands, RB101 induces these behaviors through receptor-selective activity. The antinociceptive effects of RB101 are produced through either the mu-opioid receptor alone or through activation of both mu- and delta-opioid receptors; the antidepressant-like and anxiolytic effects of RB101 are mediated only through the delta-opioid receptor. Although little is known about the effects of RB101 on other physiologically and behaviorally relevant peptides, these findings suggest that RB101 and other inhibitors of enkephalin-degrading enzymes may have potential as novel therapeutic compounds for the treatment of pain, depression, and anxiety.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75003/1/j.1527-3458.2007.00011.x.pd

Design, Synthesis, and Biological Activity of 5\u27-Phenyl-1,2,5,6-tetrahydro-3,3\u27-bipyridine Analogues as Potential Antagonists of Nicotinic Acetylcholine Receptors

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a – 3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then make subsequent modifications on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist which is highly selective for α3β4 nAChR (Ki = 123 nM) over the α4β2, and α7 receptors

Tolerance to highâ internalizing δ opioid receptor agonist is critically mediated by arrestin 2

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144602/1/bph14353.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144602/2/bph14353_am.pd

Selectivity and anti-Parkinson's potential of thiadiazolidinone RGS4 inhibitors

Many current therapies target G protein coupled receptors (GPCR), transporters, or ion channels. In addition to directly targeting these proteins, disrupting the protein−protein interactions that localize or regulate their function could enhance selectivity and provide unique pharmacologic actions. Regulators of G protein signaling (RGS) proteins, especially RGS4, play significant roles in epilepsy and Parkinson’s disease. Thiadiazolidinone (TDZD) inhibitors of RGS4 are nanomolar potency blockers of the biochemical actions of RGS4 in vitro. Here, we demonstrate the substantial selectivity (8- to >5000-fold) of CCG-203769 for RGS4 over other RGS proteins. It is also 300-fold selective for RGS4 over GSK-3β, another target of this class of chemical scaffolds. It does not inhibit the cysteine protease papain at 100 μM. CCG-203769 enhances Gαq-dependent cellular Ca2+ signaling in an RGS4-dependent manner. TDZD inhibitors also enhance Gαi-dependent δ-OR inhibition of cAMP production in SH-SY-5Y cells, which express endogenous receptors and RGS4. Importantly, CCG-203769 potentiates the known RGS4 mechanism of Gαi-dependent muscarinic bradycardia in vivo. Furthermore, it reverses raclopride-induced akinesia and bradykinesia in mice, a model of some aspects of the movement disorder in Parkinson’s disease. A broad assessment of compound effects revealed minimal off-target effects at concentrations necessary for cellular RGS4 inhibition. These results expand our understanding of the mechanism and specificity of TDZD RGS inhibitors and support the potential for therapeutic targeting of RGS proteins in Parkinson’s disease and other neural disorders

Separation of the convulsions and antidepressant-like effects produced by the delta-opioid agonist SNC80 in rats

Delta-opioid agonists produce a number of behavioral effects, including convulsions, antinociception, locomotor stimulation, and antidepressant-like effects. The development of these compounds as treatments for depression is limited by their convulsive effects. Therefore, determining how to separate the convulsive and antidepressant-like characteristics of these compounds is essential for their potential clinical use.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46370/1/213_2005_Article_138.pd

The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats

Exposure to extreme stress has been suggested to produce long-term, detrimental alterations in the hypothalamic–pituitary–adrenal (HPA) axis leading to the development of mental disorders such as depression. Therefore, compounds that block the effects of stress hormones were investigated as potential therapeutics for depression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46365/1/213_2005_Article_2164.pd

Antidepressant effects of the nonpeptidic delta -opioid receptor agonist SNC80.

The present study investigated the antidepressant-like effects of the nonpeptidic delta-opioid receptor agonist [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC80) in Sprague-Dawley rats and examined the relation between the antidepressant properties and the stimulant, convulsive, and seizurogenic effects of SNC80. In order to measure the antidepressant-like effects, behaviors were measured in the forced swim test following acute or repeated SNC80 administration. The forced swim test is a behavioral assay used to identify compounds that have similar effects to known antidepressants. This procedure has good predictive validity for identifying compounds that are successful antidepressants in humans. Other measures were collected from rats including convulsions measured by observation and locomotor and electroencephalographic activity measured by telemetry systems. Additionally, some ex vivo competition and [ 35S]GTPgammaS binding experiments were conducted to further augment observed behavioral changes. Using these experimental paradigms, the antidepressant-like effects of the delta-opioid agonists SNC80 were compared to determine the interdependence of the drug-induced effects. These studies demonstrated that the molecular structure modifications of SNC80 altered the convulsive effects of nonpeptidic delta-opioid agonists, suggesting that novel compounds or changes in existing compound structures might identify drugs that have antidepressant activity without producing convulsions. In addition to developing new compounds, the convulsions and antidepressant properties were separable based on differential sensitivity to tolerance development and infusion speed. For example, repeated SNC80 administration produced tolerance to the convulsive and locomotorstimulating effects; however, tolerance did not develop to the antidepressant-like effects of SNC80. Also, decreasing infusion rates of SNC80 nearly eliminated convulsions without altering the antidepressant-like effects of SNC80. Although the antidepressant effects were independent of delta-opioid agonist-induced behavioral convulsions, nonconvulsive seizures might contribute to the SNC80-induced antidepressant activity. However, lower doses of SNC80 that produced antidepressant effects did not produce nonconvulsive seizures. Tolerance also developed to the SNC80-induced epileptiform activity with repeated administration without affecting antidepressant properties of SNC80. In conclusion, these data demonstrated that the antidepressant activity was independent from the locomotor-stimulating, convulsive, and seizurogenic effects of the nonpeptidic delta-opioid agonist SNC80. These findings suggest that nonpeptidic delta-opioid agonists may have therapeutic potential for treating depression in humans.Ph.D.Health and Environmental SciencesPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124705/2/3150231.pd

Multiple DSM‐5 substance use disorders: A national study of US adults

ObjectiveOur aim is to determine the lifetime and past‐year prevalence estimates of multiple Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM‐5) substance use disorders (SUDs) among U.S. adults.MethodsThe 2012–2013 National Epidemiologic Survey on Alcohol and Related Conditions featured in‐person interviews with a nationally representative sample of adults aged 18 and older.ResultsThe majority of past‐year nonalcohol DSM‐5 SUDs had at least 1 other co‐occurring past‐year SUD, ranging from 56.8% (SE = 3.4) for past‐year prescription opioid use disorder to 97.5% (SE = 2.7) for past‐year hallucinogen use disorder. In contrast, only 15.0% (SE = 0.6) of past‐year alcohol use disorders had a co‐occurring past‐year SUD. The odds of past‐year multiple SUDs were greater among males, younger adults, African‐Americans, and those with mood, personality, posttraumatic stress, or multiple psychiatric disorders.ConclusionsAssessment, diagnosis, and treatment often focus on individual substance‐specific SUDs rather than multiple SUDs, despite evidence for substantial rates of polysubstance use in clinical and epidemiological studies. There are notable differences in the prevalence of multiple SUDs between alcohol use disorders and other nonalcohol SUDs that have important clinical implications; for example, multiple SUDs are more persistent than individual SUDs. These findings suggest that clinical assessment and diagnosis should screen for multiple SUDs, especially among adults with nonalcohol DSM‐5 SUDs.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138251/1/hup2625_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138251/2/hup2625.pd