We show that carbohydrates constitute an attractive source of readily available, stereochemically defined scaffolds for the facile attachment of side chains contained in genetically encoded and other amino acids. beta-D- and beta-L-glucose, L-mannose, and the 6-deoxy-6-N-analogue of beta-D-glucose have been employed to synthesize peptidomimetics that bind the SRIF receptors on AtT-20 mouse pituitary cells, five cloned human receptor subtypes (hSSTRs), and the NK-1 receptor. The affinity profile of various sugar-based ligands at the hSSTRs is compared with that of SRIF. Compound 19 bound hSSTR4 with a Ki of 100 nM. Subtle structural changes affect affinities. Evidence is presented that suggests that one compound (8) binds both the AtT-20 cell receptors and the five hSSTRs via a unique mode. The SARs of the glycosides at SRIF receptors differ markedly from those at the NK-1 receptor. For example a 4-benzyl substituent is important for SRIF receptor binding, but the 4-desbenzyl analogue 27 was highly potent (IC50 of 27 nM) at the NK-1 receptor. A new, nonbasic method for the synthesis of base-sensitive ethers from primary and secondary alcohols is also described.

During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.

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www.sbsonline.org 789 INTRODUCTION G-protein-coupled receptors (Gpcrs) constitute the larGest family of cell surface receptors that respond to a wide range of extracellular stimuli and are involved in virtually all known physiological processes in mammals.1 Although they respond to diverse agonists, the structural and functional features of these receptors are remarkably conserved. All GPCRs have 7 transmembrane domains and activate a variety of G-protein signaling pathways upon agonist stimulation.1,2 There are 4 major Gα protein subfamilies: Gα s , Gα i/o , Gα q , and Gα 12/13 . Gα s stimulates adenylyl cyclase and increases cyclic AMP (cAMP) production, whereas Gα i inhibits cAMP production. Activation of Gα q stimulates phospholipase C β followed by production of diacylglycerol and inositol phosphate, which initiates calcium release from intracellular stores.Even though GPCRs constitute only a small fraction (15%) of total druggable genes, they account for more than 30% of targets of marketed small-molecule drugs.3 Due to the enormous historical success of GPCR drug targets, the search for new drugs targeting GPCRs is still the prime focus of many pharmaceutical companies. The completion of the human genome sequence project revealed more than 800 GPCR sequences, of which around 140 GPCRs, excluding olfactory receptors, are still classified as orphan receptors, (i.e., receptors with ligand and physiological functions unknown).4,5 Some of these uncharacterized orphan receptors are likely to be novel therapeutic targets of the future.6,7 Over the past 2 decades, more than 100 receptors have been deorphanized (i.e., paired with their endogenous ligands). 6,8 The deorphanization of once-orphaned GPCRs has proven to be fruitful and already unveiled several exciting novel drug targets for treating human diseases, including neurological and neurodegenerative disorders, sleep disorders, inflammation, and rheumatoid arthritis. 6,7,[9][10][11] Human GPR139 (also called hGPCR12, GPRg1, and PGR3) is an orphan receptor that was first described as a receptor homologous to thyrotropin-releasing hormone receptor. 12,13 GPR139 is extremely well conserved, as the protein sequence of the human receptor is 96% identical to both mouse and rat orthologs. GPR139 shows distant homology to a variety of peptide and chemokine receptors with identities in the range of

The design and synthesis of two pyrrolinone−peptide hybrid ligands (3 and 20) for the rheumatoid arthritis-associated class II MHC HLA-DR1 protein are described. The hybrids incorporate bispyrrolinones 4 and 21 as tetrapeptide mimics for amino acids VKQN (residues 309−312) of the virus hemagglutinin peptide HA 306−318 (PKYVKQNTLKLAT). Ligand construction employed our polypyrrolinone synthetic protocol, in conjunction with Fmoc-based solid-phase peptide synthesis. Bioaffinity studies reveal that hybrid ligand 3 bound the HLA-DR1 protein with affinity (IC50 = 137 nM) comparable to those of both the native HA 306−318 peptide (IC50 = 89 nM) and a control peptide (IC50 = 176 nM). This result demonstrates that the polypyrrolinone scaffold can be employed in the construction of bioactive peptide hybrid ligands, thus considerably expanding the scope and utility of the pyrrolinone scaffold.