In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl-and 2-OCH 3 -phenyl piperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R-and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported to date that show high affinity (K i =1 nM) for D3 and ∼400-fold selectivity over the D2 receptor subtype. Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors further underscoring their value as in vivo research tools. These lead compounds also have appropriate physical characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders. Keywordsdopamine; D3 receptor; cocaine; drug abuse; addiction The dopamine D3 receptor, a member of the dopamine D2-like receptor family, has become a target of intensive research over the past decade due to several features that have revealed its potential for development of medications toward neuropsychiatric disorders, dyskinesias associated with L-DOPA treatment of Parkinson's disease, and drug addiction. [1][2][3] Numerous studies have been published that implicate the dopamine D3 receptors in animal models of these disorders. However, many of the pharmacological tools that have been available for in vivo investigation cannot rule out other possible underlying mechanisms of action, due to lack γ This manuscript is dedicated to the memory of my dear friend and colleague, Dr. Andrew Thurkauf, who first introduced me to the dopamine D3 receptor antagonists more than a decade ago. *anewman@intra.nida.nih.gov; phone: (443) 740-2887; Fax: (443) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of D3 receptor selectivity, poor bioavailability, or predicted toxicity that precludes human testing. Indeed, another complicating factor is that although functional coupling of D3 receptors to G αi/o -proteins has been established, 4,5 the question of which G-protein signaling pathways are recruited by D3 receptor activation in vivo remains unanswered.Nevertheless, the fact that several D3 antagonists have demonstrated efficacy in animal models of drug abuse without the concomitant motor side effects associated with nonselective D2 antagonists, supports further pursuit of the D3 receptor as a potential target for medication development. One of the single most important drivers of this research is the medicinal chemistry that has ultimately broken the barriers of nonselective D2/D3 ligands and enabled the discovery of high affi...

In recent years, reaction of inexpensive and abundantly available alcohols (C-OH) with unactivated nucleophilic coupling partners (C-H), leading to the construction of the C-C bond, has emerged as one of the vital strategies since it is an atom-economical and environmentally benign approach with water as the by-product. Various transition metal-catalyzed or metal-free approaches for the direct dehydrative coupling employing the C-OH bond (including in situ activation) have recently been devised. This review article aims to highlight advances in such waste-free C-C bond forming dehydrative strategies.

To test the hypothesis that hyaline membrane disease (HMD) has a multifactorial etiology in which barotrauma plays a major role, we compared the immediate institution of high-frequency oscillatory ventilation (HFOV; 15 Hz, n = 5) with positive-pressure ventilation with positive end-expiratory pressure (PPV; n = 7) in premature baboons (140-days gestation) with HMD. Measurements of ventilation settings and physiological parameters were obtained and arterial-to-alveolar O2 (PaO2-to-PAO2) ratio and oxygenation index [(PaO2/PAO2)-to-mean airway pressure ratio (IO2)] were calculated. At death (24 h), static pressure-volume (PV) curves were performed, and phospholipids (PL) and platelet-activating factor (PAF) were measured in lung lavage fluid. Morphological inflation patterns were analyzed using a panel of standards. By design, mean airway pressure was initially higher (19 vs. 13 cmH2O) in the HFOV animals. PaO2-to-PAO2 ratio and IO2 progressively deteriorated in the PPV animals and then stabilized at significantly lower levels than with HFOV. PV curves from HFOV animals had significant increases in lung volume at maximum distending pressure, deflation volume at 10 cmH2O, and hysteresis area compared with PPV, which showed no hysteresis. Seven of seven PPV and only one of five HFOV animals had morphological findings of HMD. PL amount and composition in both groups were consistent with immaturity, even though the quantity was significantly greater in the PPV group. PAF was present (greater than or equal to 0.10 pmol) in six of seven PPV and in the only HFOV animal with HMD. We conclude that HFOV protected PL-deficient premature baboons from changes in gas exchange, lung mechanics, and morphology typical of HMD in this model.(ABSTRACT TRUNCATED AT 250 WORDS)