ABSTRACT
Enantiomeric N-phenethyl-m-hydroxyphenylmorphans with various substituents in the ortho, meta or para positions of the aromatic ring in the phenethylamine side-chain (chloro, hydroxy, methoxy, nitro, methyl), as well as a pyridylethyl and a indolylethyl moiety on the nitrogen atom, were synthesized and their binding affinity to the mu-, delta-, and kappa-opioid receptors was examined. The higher affinity ligands were further examined in the [(35)S]GTPgammaS assay to study their function and efficacy. 3-((1R,5S)-(-)-2-(4-Nitrophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((-)-) was found to be a mu-agonist and delta-antagonist in that functional assay and was about 50 fold more potent than morphine in vivo. 3-((1R,5S)-(-)-2-(4-Chlorophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((-)-) and several other ligands displayed inverse agonist activity at the delta-opioid receptor. The absolute configuration of all of the reported compounds was established by chemical conversion of (-)- to 1R,5S-(-)-.HBr.
Subject(s)
Morphinans/chemical synthesis , Morphinans/pharmacology , Receptors, Opioid, delta/agonists , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid, mu/agonists , Animals , Binding, Competitive/drug effects , CHO Cells , Cricetinae , Cricetulus , Ligands , Morphinans/chemistry , Receptors, Opioid, delta/chemistry , Receptors, Opioid, mu/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
BACKGROUND: Alcohol dependence is characterized by excessive alcohol consumption, loss of control over intake, and the presence of a withdrawal syndrome, which includes both motivational and physical symptoms. Similar to human alcoholics, ethanol-dependent animals display enhanced anxiety-like behaviors and enhanced ethanol self-administration during withdrawal, effects hypothesized to result from a dysregulation of corticotropin-releasing factor (CRF) stress systems. Here, we used an animal model of ethanol dependence to test the effects of CRF(1) receptor antagonists on excessive ethanol self-administration in dependent rats. METHODS: Wistar rats, trained to orally self-administer ethanol, were exposed intermittently to ethanol vapors to induce ethanol dependence. Nondependent animals were exposed to control air. Following a 2-hour period of withdrawal, dependent and nondependent animals were systemically administered antalarmin, MJL-1-109-2, or R121919 (CRF(1) antagonists) and ethanol self-administration was measured. RESULTS: The nonpeptide, small molecule CRF(1) antagonists selectively reduced excessive self-administration of ethanol in dependent animals during acute withdrawal. The antagonists had no effect on ethanol self-administration in nondependent rats. CONCLUSIONS: These data demonstrate that CRF(1) receptors play an important role in mediating excessive ethanol self-administration in dependent rats, with no effect in nondependent rats. CRF(1) antagonists may be exciting new pharmacotherapeutic targets for the treatment of alcoholism in humans.
Subject(s)
Alcoholism/drug therapy , Alcoholism/psychology , Central Nervous System Depressants/administration & dosage , Corticotropin-Releasing Hormone/antagonists & inhibitors , Ethanol/administration & dosage , Hormone Antagonists/therapeutic use , Animals , Behavior, Animal/drug effects , Conditioning, Operant/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Hormone Antagonists/chemistry , Male , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Rats , Rats, Wistar , Self Administration/methods , Triazines/therapeutic useABSTRACT
A high-affinity, nonpeptide radioligand for the CRHR1 was synthesized and showed distribution in rat brain consistent with CRHR1 using in vitro autoradiography. This is the first nonpeptide radiotracer combining high affinity and appropriate lipophilicity that penetrates the blood-brain barrier and hence has the potential to be used for PET imaging studies. In vivo visualization of changes in the CRH1 receptor or its occupancy would further the understanding of the pathophysiology of stress related diseases.
