Scientific Report 2006

Chemistry

Translational Chemistry and Medicine

E. Roberts, Z.Y. Chen, O. Ghoneim, C. Martinez, S. Sinha, C. Zoni

Discovery and development of new medicines require the integration of several scientific disciplines. For example, medicinal chemistry relies on iterative in vitro and in vivo biological testing of molecules. These biological investigations, in turn, rely on the design and synthesis of new molecules with therapeutic potential to delineate and validate pathways for therapeutic intervention. The primary focus of our research is to identify potential new medicines for the treatment of diseases that currently have inadequate or no current therapy.

Galanin Ligands for the Treatment of Neurologic Diseases

Epilepsy is a disease in which a hyperexcited state of the CNS is caused by an imbalance between inhibitory and excitatory neurotransmission. Current epilepsy therapy focuses on modulating the classical neurotransmitters glutamate and γ-aminobutyric acid. The neuropeptide galanin antagonizes excitatory glutaminergic neurotransmission in the hippocampus, suggesting that galanin may have a role in seizure activity. Galanin and its receptors may be useful in developing novel antidepressant pharmacotherapies. In a recent study in humans with depression, intravenously administered galanin had a rapid and strong antidepressant effect.

To identify new nonpeptidic ligands for galanin receptors, we are using a small set of known molecules that can potently displace the peptide galanin from its binding site on the R3 receptor subtype. Selectivity and potency can then be established by appending appropriate accessory binding motifs selective for the desired protein. This research is being done in collaboration with T. Bartfai, Molecular and Integrative Neurosciences Department, and A.M. Mazarati, University of California, Los Angeles.

Dual Opioid Agonists–Cholecystokinin Antagonists for Treatment of Chronic and Neuropathic Pain

Nociception, or the perception of pain, and its modulation depend on the interaction of many endogenous neurotransmitters in the spinal cord. The interaction of endogenous peptides such as cholecystokinin with exogenously administered opioids markedly alters activity in acute and chronic pain states. Cholecystokinin antagonizes the analgesic effects of morphine, whereas cholecystokinin antagonists enhance them. The interplay between cholecystokinin antagonists and opiates may lead to the development of novel medications that are more effective and safer than currently used opioids alone.

Molecules with both opioid agonist and cholecystokinin antagonist properties would be useful in conditions in which the effectiveness of opioids is reduced, as in the development of tolerance to opiate pain relievers in chronic pain associated with cancer. The molecules might also be useful in neuropathic pain conditions in which opioids are ineffective. Thus, because of the prevention (or reversal) of tolerance, the possibility of physical dependence on opioids might be diminished or inhibited. The advantages of developing a single compound with dual opioid agonist–cholecystokinin antagonist activity rather than a combination of an opioid agonist taken with a separate cholecystokinin antagonist are clear. Development of a single compound involves only a single set of parameters, such as toxicology, pharmacokinetics, and formulation, rather than 2 independent and often unrelated sets of data.

In collaboration with F. Porreca and J. Lai, University of Arizona, Tucson, we are using a limited set of molecular templates that have affinity across a wide range of type 1 G protein–coupled receptors. The 3 cloned opiate receptors (μ, δ, and κ) and the cholecystokinin 1/(A) and 2/(B) receptors are all members of this subclass of G protein–coupled receptors. Ligands are known for both sets of receptors that contain the diphenylmethyl moiety as a privileged or biased template. Other critical elements for activity may be appended to chemically “silent” sites (Fig. 1).

Neuropharmacologic Approaches for Prevention and Treatment of Autism

Autism is a bioneurologic developmental disability that generally appears before the age of 3 years. This disability affects the normal development of the brain in the areas of social interaction, communication skills, and cognitive function. The prevalence of autistic diseases has reached pandemic proportions. In the United States, autism occurs in an estimated 1 in 166 births, and roughly 1.5 million persons have some form of autism. This rate is increasing significantly and now surpasses that of all types of cancer combined.

Fig. 1. Proposed opioid agonist–cholecystokinin antagonist hybrids.

No drug is consistently effective in treating the signs and symptoms of autism. Vasopressin and oxytocin are 2 nonapeptides (Fig. 2) secreted by the hypothalamus. They differ in only 2 amino acids, and both exert their effects at protein receptors that belong to the G protein–coupled receptor superfamily, namely vasopressin V1a, V1b, and V2 receptors and oxytocin receptors. When oxytocin and vasopressin exert their agonist effects at the oxytocin and vasopressin V1a receptors, respectively, in rodents, marked effects occur in the CNS. These effects include behaviors associated with autism, such as social behaviors (e.g., bonding, aggression); cognition (e.g., memory and active-passive avoidance); and repetitive, patterned movements (e.g., grooming or social interaction). Antagonists reverse or have no effect on the observed behaviors.

Fig. 2. Structures of vasopressin and oxytocin.

We are designing and developing small-molecule oxytocin agonists that can penetrate the CNS and previously unknown vasopressin V1a receptor agonists to establish the potential roles for these molecules in the treatment of autism (Figs. 3 and 4). This research is being done in collaboration with T. Bartfai, G.F. Koob, and A. Roberts, Molecular and Integrative Neurosciences Department.

Fig. 3. A, Known mixed vasopressin V1a/V2 receptor antagonists. B, Known vasopressin V1a receptor antagonists.

Fig. 4. Known oxytocin receptor agonists.

Publications

Roberts, E., Sancon, J.P., Sweeney, J.B. A new class of ammonium ylid for [2,3]-sigmatropic rearrangement reactions: end-endo-spiro ylids. Org. Lett. 7:2075, 2005.

Workman, J.A., Garrido, N.P., Sancon, J., Roberts, E., Wessel, H.P., Sweeney, J.B. Asymmetiric [2,3]-rearrangement of glycine-derived allyl ammonium ylids. J. Am. Chem. Soc. 127:1066, 2005.