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There is considerable interest in designing synthetic catalysts that can hydrolyze phosphate diesters" -3 1 since such artificial nucleases have potential applications as novel antiviral and anticancer therapeutic agent^.[^-^] An important strategy for developing artificial enzymes is to incorporate, into a synthetic framework. functional groups known to be present in the enzyme's active site and that are essential for maintaining catalytic activity. The DNA and RNA hydrolyzing enzyme, staphylococcal nuclease (SN), contains two key arginine residues, Arg35 and Arg87, in its active site."] Site directed mutagenesis studies have establishedr8-101 that only one arginine residue (Arg35) binds to the monoanionic substrate, but both residues are required for phosphate ester hydrolysis. In an attempt to exploit this important feature of SN, weI1'l and othersr1'-'*] have designed mono-and bis(guanidinium) derivatives that bind with phosphate diesters in organic solvents. We have shown that certain bis(guanidinium) receptors can mimic SN and accelerate the transesterification of phosphate diesters. A key requirement for these guanidinium receptors[1y1 and related systemsL2, 2 0 , ''I is the addition of a general base (e.g. lutidine, tetramethylguanidine. imidazole) to deprotonate the hydroxyl nucleophile (Scheme 1 , A). In an attempt to design a receptor that contains H 0 H 02" \ Scheme 1 . Transesterification of HPNPP mediated by bis(guanidinium) receptors and an added base (A) and by a bis(guanid1nium) receptor with an appended basic group ( B i .all the necessary components for catalysis, we have linked general base groups to the bis(guanidinium) receptors. The receptor design is based on bis(a1kylguanidinium) derivatives that remain protonated in the presence of a wide range of basic groups. These receptors can potentially accelerate phosphate ester cleavage by providing a hydrogen-bonding cleft to increase the electrophilicity and facilitate nucleophilic attack on phosphorus upon binding in the manner depicted in Scheme 1, B. In this paper we report a series of alkylguanidinium ions 1-5 containing appended nitrogen bases and compare their efficiencies in accelerating the transesterification reaction of the RNA model, 2-hydroxypropyl-para-nitrophenylphosphate (HPNPP) .[22s 231 ) Telefdx. Int. code +(41?) 624-8552 [**I This work was supported by the U.S. Office of Naval Research. A n p i C'iwm. Inr. Ed. Engl. 1995, 34. N o . I 1 :<) VCH Verlugsgesrllscliu/,/r mhH, D-6Y45I Weinhein!, 1995 0570-0833iYSillll-/237 S I(J.(JO+ . 3 ; 0 C? VCH V e r l a~s~a s e l l s~~l i u~t mhH, D-69451 Wrinhrim 1995 0570-083S~9S~iiIi-1~3X S 1 O . O O i .25/0 Angeu'. Chem. In[. Ed. EngI. 1995, 34. No. I ! of HPNPP [ZY]. The rate constants were obtained by fitting at least three half-lives of the reaction according to a first-order kinetics equation. For slower reactions. rate conslants were calculated from the initial rates. First-order rate constants were calculated from the slopes of the linear plots of absorbance versus time by convertin...

Recently there has been great success in the generation of large libraries of synthetic ligands1 via linear sequences of chemical transformations (e.g., peptides,2 oligonucleotides,3 benzodiazepines,4 etc.). In the main these have been small molecules used for binding into the active sites of biological receptors. The strategy is less applicable to synthetic molecules

Neuropeptide Y (NPY) regulates physiological processes via receptor subtypes (Y 1 , Y 2 , Y 4 , Y 5 , and y 6 ). The Y 5 receptor is well known for its role in appetite. Based on expression in the limbic system, we hypothesized that the Y 5 receptor might also modulate stress sensitivity. We identified a novel Y 5 receptorselective antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro ]-hPancreatic Polypeptide. In Sprague-Dawley rats subjected to the social interaction test, Lu AA33810 (3-30 mg/kg p.o.) produced anxiolyticlike effects after acute or chronic treatment. In Flinders sensitive line rats, chronic dosing of Lu AA33810 (10 mg/kg/day i.p.) produced anxiolytic-like effects in the social interaction test, plus antidepressant-like effects in the forced swim test. In Wistar rats exposed to chronic mild stress, chronic dosing of Lu AA33810 (3 and 10 mg/kg/day i.p.) produced antidepressant-like activity, i.e., normalization of stress-induced decrease in sucrose consumption. We propose that Y 5 receptors may function as part of an endogenous stress-sensing system to mediate social anxiety and reward or motivational deficits in selected rodent models.Neuropeptide Y (NPY) is a 36-amino acid transmitter belonging to the pancreatic polypeptide family, along with peptide YY (PYY) and pancreatic polypeptide (PP). NPY has widespread distribution throughout the central nervous system and periphery and has been demonstrated to modulate numerous physiological processes (e.g., appetite, metabolism, mood, and reproduction) via G protein-coupled receptors (primarily G i/o type). Receptor subtypes for NPY and relatedThe authors are affiliated with Lundbeck Research USA as either employees or paid collaborators. Lundbeck has a research program to study the therapeutic potential of the Y 5 receptor as a drug target.