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BACKGROUND A history of alcohol dependence recruits increased voluntary alcohol intake and sensitivity to stress. Corticotropin-releasing hormone (CRH) has been implicated in this transition, but underlying molecular mechanisms remain unclear. METHODS A postdependent state was induced using intermittent alcohol exposure. Experiments were carried out(More)
An increasingly competitive pharmaceutical market demands improvement in the efficiency and probability of drug candidate discovery. Usually these new drug candidates are targeted for oral administration, so a detailed understanding of the molecular-level properties that relate to optimal pharmacokinetics is a critical step toward improving the probability(More)
The three peptides pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY) share a similar structure known as the PP-fold. There are four known human G-protein coupled receptors for the PP-fold peptides, namely Y1, Y2, Y4, and Y5, each of them being able to bind at least two of the three endogenous ligands. All three peptides are found in(More)
This article summarizes the proceedings of a symposium held at the conference on "Alcoholism and Stress: A Framework for Future Treatment Strategies" in Volterra, Italy, May 6-9, 2008. Chaired by Markus Heilig and Roberto Ciccocioppo, this symposium offered a forum for the presentation of recent data linking neuropetidergic neurotransmission to the(More)
We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-sauvagine binding to rat pituitary membranes(More)
A set of nine 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides and one 2,6-dimethylimidazo[1,2-a]pyrimidine-3-carboxamide were synthesized. The compounds were evaluated for their in vitro anti-tuberculosis activity versus replicating, non-replicating, multi- and extensive drug resistant Mtb strains. The MIC(90) values of seven of these agents were ≤ 1 μM(More)
LY303870 is a competitive, high affinity NK-1 receptor antagonist. It was tested in the trigeminal stimulation-induced neurogenic dural inflammation model of migraine. The neurogenic inflammation theory of migraine pain proposes that substance P, acting through NK-1 receptors, causes dural inflammation which enhances migraine pain. LY303870 administration(More)
We conducted an evaluation of the phenoxyalkylbenzimidazole series based on the exemplar 2-ethyl-1-(3-phenoxypropyl)-1H-benzo[d]imidazole for its antitubercular activity. Four segments of the molecule were examined systematically to define a structure-activity relationship with respect to biological activity. Compounds had submicromolar activity against(More)
Lanepitant, a potent non-peptide neurokinin-1 receptor antagonist, inhibits neurogenic dural inflammation, and may have a role in migraine therapy. This study evaluated the effect of lanepitant taken daily for migraine prevention. Patients with migraine headaches with and without aura by International Headache Society classification criteria were enrolled(More)
The selective neurokinin (NK)-1 antagonist LY303870 has high affinity and specificity for human and guinea pig brain NK-1 receptors labeled with 125I-substance P. It has approximately 15- to 30-fold lower affinity for rat and mouse brain NK-1 receptors, consistent with previously reported species differences in the affinities of nonpeptide antagonists for(More)