I use medicinal chemistry to develop a better understanding of the molecular mechanisms underlying neuropsychological diseases, in particular drug abuse, but also including depression and anxiety. To this end, both highly selective ligands and, more recently, ligands targeted at multiple receptors are designed and synthesized, along with specific pharmacological tools such as irreversible and radiolabeled ligands which allow us to study changes in the chemistry of the brain. Manipulation of the duration of activity of ligands has also been a theme within recent years. I am also interested in the therapeutic potential of such compounds, in particular the group is continuing to study, with the help of funding from the National Institute on Drug Abuse, the utility of opioid ligands as treatment agents for opioid, cocaine and other drugs of abuse and the use of opioid ligands in the treatment of depression. The most important work within the group has been towards ‘selectively promiscuous’ ligands and has been driven by the realisation that CNS disorders are rarely simple, requiring complex solutions. Particular success, and impact, has been achieved in delineating the molecular descriptors that are crucial to the unique pharmacological profile displayed by the opioid treatment agent buprenorphine. This work has allowed us to develop ligands that target multiple opioid receptors simultaneously, with some control over efficacy at each receptor. Current targets include the mu, kappa and NOP opioid receptors and, separately, Regulators of G protein Signaling (RGS) proteins. All our work is carried out in collaboration with colleagues at the University of Bath, the University of Michigan, Torrey Pines Institute for Molecular Studies, Imperial College and the University of Bristol. Current and recent funding for our work has come from the National Institute on Drug Abuse, the Medical Research Council and the Cystic Fibrosis Trust.