J Mol model(2006)12:877-884 DOI10.1007/00894005-00849 ORIGINAL PAPER Wei li· Yun Tang Qiong Xie· Wei sheng Zhui-Bai Qiu 3D-QSAR studies of orvinol analogs as k-opioid agonists Received: 14 April 2005/ Accepted: 11 November 2005/ Published online: 22 March 2006 c) Springer-Verlag 2006 Abstract Orvinols are potent analgesics that target opioid 1960-1970s, and some of them were several thousand receptors. However, their analgesic mechanism remains times more potent than morphine in analgesic assays of the unclear and no significant preference for subtype opioid rat tail pressure test [1, 2]. Similar to morphine, their receptor has been achieved. In order to find new orvinols biological targets were suggested to be opioid receptors that target the K-receptor, comparative 3D-QSAR studies However, because opioid receptors had not been identified were performed on 26 orvinol analogs using comparative at that time, the detailed analgesic mechanism was difficult molecular field analysis( CoMFA)and comparative mo- to elucidate. Furthermore, only rodent antinociceptive lecular similarity indices analysis(CoMSIA). The best pre- models were available to evaluate the analgesic effects of dictions for the K-receptor were obtained with the CoMFa newly prepared compounds standard model(q-=0.686, r=0.947)and CoMSIA model Until the early 1990s as opioid receptors were cloned combined steric, electrostatic, hydrophobic, and hydrogen gradually, at least three subtypes u, 8 and K were identified, bond donor/acceptor fields ((=0.678, r2=0.914). The which greatly facilitated studies of opioid receptors and models built were further validated by a test set made up their ligands. Typical analgesics, such as morphine and 0.672 for CoMFA and 0.593 for CoMSIA. The study could ever, it has long been recognized that H-opioids have some e helpful for designing and prepare new category notorious side effects such as respiratory depression, drug K-agonists from orvinols cuon ane nd dependence. Recent studies on the k-opioid receptor revealed that k-agonists show potent analgesic Keywords k-opioid agonists. Opiate analgesics effects but lack the above-mentioned side effects which COMFA· COMSIA indicate that k-selective agonists might be developed as a new generation of analgesics without addiction [3, 4] As semi-synthetic opiates, orvinols also target multiple Introduction opioid receptors with diverse efficacy profiles [5]. Howev er, BU46, one of the orvinols, displayed some K-like Orvinols, derived from the structure of thebaine are potent induced analgesic mechanism in vivo [6]. In order to nalgesic. Their structure and activity relationships were investigate K-selective agonists, since the late 1990s thoroughly investigated by Bentley and Colman in the Lewis, successor of Bentley, has focused on orvinols and synthesized a large number of new derivatives and struc s of BU46. They then proposed a tri w.Li·Y.Tang:Q.Xie·w. Sheng:Z.-B.Qiu binding-site model [7] to explain the pharmacological Department of Medicinal Chemistry, School of Pharmac phenomena of orvinols on k-receptor, in combination with niversity other moderately k-selective compounds derived from ori vinous(Fig. 1, except for KT-95 and TRK-820)[8-10] and 32, People's Republic of China all structure-activity relationship (SAR) analyses were carried out qualitatively on these orvinols Therefore in this paper, in order to guide the synthesis of hool of Pharmacy, East China University of Science Technology new orvinol derivatives as k-specific agonists, we in- vestigated orvinol analogs with comparative 3D-QSAR Shanghai 200237, People's Republic of China methods in order to inspect the 3D-QSAR for the same e-mail: yang 234@ yahoo. series of compounds with affinities against the k-opioid Tel:+86-21-54237419 receptor, using comparative molecular field analysisJ Mol Model (2006) 12: 877–884 DOI 10.1007/s00894-005-0084-9 OR IG INAL PAPER Wei Li . Yun Tang . Qiong Xie . Wei Sheng . Zhui-Bai Qiu 3D–QSAR studies of orvinol analogs as κ-opioid agonists Received: 14 April 2005 / Accepted: 11 November 2005 / Published online: 22 March 2006 # Springer-Verlag 2006 Abstract Orvinols are potent analgesics that target opioid receptors. However, their analgesic mechanism remains unclear and no significant preference for subtype opioid receptor has been achieved. In order to find new orvinols that target the κ-receptor, comparative 3D–QSAR studies were performed on 26 orvinol analogs using comparative molecular field analysis (CoMFA) and comparative mo￾lecular similarity indices analysis (CoMSIA). The best pre￾dictions for the κ-receptor were obtained with the CoMFA standard model (q 2 =0.686, r 2 =0.947) and CoMSIA model combined steric, electrostatic, hydrophobic, and hydrogen bond donor/acceptor fields (q 2 =0.678, r 2 =0.914). The models built were further validated by a test set made up of seven compounds, leading to predictive r 2 values of 0.672 for CoMFA and 0.593 for CoMSIA. The study could be helpful for designing and prepare new category κ-agonists from orvinols. Keywords κ-opioid agonists . Opiate analgesics . CoMFA . CoMSIA Introduction Orvinols, derived from the structure of thebaine, are potent analgesics. Their structure and activity relationships were thoroughly investigated by Bentley and Colman in the 1960–1970s, and some of them were several thousand times more potent than morphine in analgesic assays of the rat tail pressure test [1, 2]. Similar to morphine, their biological targets were suggested to be opioid receptors. However, because opioid receptors had not been identified at that time, the detailed analgesic mechanism was difficult to elucidate. Furthermore, only rodent antinociceptive models were available to evaluate the analgesic effects of newly prepared compounds. Until the early 1990s as opioid receptors were cloned gradually, at least three subtypes μ, δ and κ were identified, which greatly facilitated studies of opioid receptors and their ligands. Typical analgesics, such as morphine and fentanyl, are found to be potent μ-opioid agonists. How￾ever, it has long been recognized that μ-opioids have some notorious side effects such as respiratory depression, drug addiction and dependence. Recent studies on the κ-opioid receptor revealed that κ-agonists show potent analgesic effects but lack the above-mentioned side effects, which indicate that κ-selective agonists might be developed as a new generation of analgesics without addiction [3, 4]. As semi-synthetic opiates, orvinols also target multiple opioid receptors with diverse efficacy profiles [5]. Howev￾er, BU46, one of the orvinols, displayed some κ-like induced analgesic mechanism in vivo [6]. In order to investigate κ-selective agonists, since the late 1990s, Lewis, successor of Bentley, has focused on orvinols and synthesized a large number of new derivatives and struc￾turally related analogs of BU46. They then proposed a triple binding-site model [7] to explain the pharmacological phenomena of orvinols on κ-receptor, in combination with other moderately κ-selective compounds derived from ori￾vinols (Fig. 1, except for KT-95 and TRK-820) [8–10] and all structure-activity relationship (SAR) analyses were carried out qualitatively on these orvinols. Therefore in this paper, in order to guide the synthesis of new orvinol derivatives as κ-specific agonists, we in￾vestigated orvinol analogs with comparative 3D–QSAR methods in order to inspect the 3D–QSAR for the same series of compounds with affinities against the κ-opioid receptor, using comparative molecular field analysis W. Li . Y. Tang . Q. Xie . W. Sheng . Z.-B. Qiu Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai 200032, People’s Republic of China e-mail: zbqiu@shmu.edu.cn Y. Tang (*) School of Pharmacy, East China University of Science & Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China e-mail: ytang234@yahoo.com.cn Tel.: +86-21-54237419