Scientific Report 2007

Chemistry

Translational Chemistry and Medicine

E. Roberts, G. Cherukupalli, O. Ghoneim, M. Morales, X. Peng, C. Zoni, S. Sinha, K. Reynolds, R. Poddutoori, Y. Wang

Discovery and development of new medicines require the integration of several scientific disciplines. 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 enhance and cooperate in applied scientific efforts with clear goals and milestones to identify potential new medicines for the treatment of diseases that currently have inadequate or no therapy.

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.

In collaboration with T. Bartfai, Molecular and Integrative Neurosciences Department, and A.M. Mazarati, University of California, Los Angeles, we have identified new nonpeptidic ligands for the galanin receptors GalR1 and GalR2. This set of small, druglike molecules can displace the peptide galanin from its protein binding site. Selectivity and potency of these initial molecular starting points are being optimized.

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 the effects. The interaction between cholecystokinin antagonists and opiates may lead to the development of novel medications that are more effective and safer than currently available 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 and in neuropathic pain conditions in which opioids are ineffective. Thus, because of the prevention (or reversal) of tolerance, physical dependence on opioids may 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 (Fig. 1).

Fig. 1. Opioid agonist–cholecystokinin antagonist hybrids.

Neuropharmacologic Approaches for Treatment of Pervasive Developmental Disorders

Autism is a bioneurologic developmental disability that affects the normal development of the brain in the areas associated with 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. This rate is increasing significantly and now surpasses that of all types of cancer combined.

No drug is consistently effective in treating the signs and symptoms of autism. The neuropeptides vasopressin and oxytocin (Fig. 2) have profound effects in rodent and sheep models of social behavior.

Fig. 2. Structures of vasopressin and oxytocin.

These models are being used to understand more fully human social deficit disorders such as the pervasive development disorders of autism and Asperger's syndrome and the effects of stress on women. The lack of CNS-accessible and subtype-selective ligands has hindered drug research and development in these areas. We are developing small-molecule, druglike agonists for the oxytocin and vasopressin V1a receptors that are selective and able to penetrate the blood-brain barrier and are testing the agonists in these models of social behavior. Our goal is to identify validated lead compounds for further preclinical development (Figs. 3 and 4). This research is done in collaboration with T. Bartfai, G.F. Koob, and A. Roberts, Molecular and Integrative Neurosciences Department.

Fig. 3. A, Known mixed vasopressin V1a/V2a receptor antagonists. B, Known vasopressin V1a antagonists.

Fig. 4. Known oxytocin receptor agonists.

Immunomodulating Compounds for the Treatment of Diseases with Uncontrolled Inflammation

In collaboration with H. Rosen and coworkers, Department of Immunology, we are investigating the sphingosine phosphate family of G protein–coupled receptors. Iterative screening/design and synthesis have yielded several extremely potent sphingosine 1-phosphate subtype agonists with low molecular weights and druglike properties (Table 1). The best of these are being characterized in in vivo models and for absorption, distribution, metabolism, excretion, and pharmacokinetic properties. These compounds are designed to be orally active and to be immunomodulating without compromising the immune response. Such molecules may find use in organ transplantation, tissue grafts, neoplastic diseases, and autoimmune disorders.

Publications

Don, A.S., Martinez-Lamenca, C., Webb, W.R., Proia, R.L., Roberts, E., Rosen, H. Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogs. J. Biol. Chem. 282:15833, 2007.