Oligonucleotide-based receptors or aptamers can interact with small molecules, but the ability to achieve high-affinity and selectivity of these interactions depends strongly on functional groups or epitopes displayed by the binding targets. Some classes of targets are particularly challenging: for example, monosaccharides have scarce functionalities and no aptamers have been reported to recognize, let alone distinguish from each other, glucose and other hexoses. Here we report aptamers that differentiate low-epitope targets such as glucose, fructose, or galactose by forming ternary complexes with high-epitope organic receptors for monosaccharides. In a follow-up example, we expand this method to isolate high-affinity oligonucleotides against aromatic amino acids complexed in situ with a non-specific organometallic receptor. The method is general and enables broad clinical use of aptamers for detection of small molecules in mix-and-measure assays, as demonstrated by monitoring postprandial waves of phenylalanine in human subjects.

Artificial receptors for hydrophobic molecules usually have moderate affinities and limited selectivities. We describe three new classes of high affinity hydrophobic receptors for nonaromatic steroids based on deoxyribonucleotides, obtained through five high stringency selections coupled with tailored counter-selections. The isolation of multiple classes of high affinity steroid receptors demonstrates the surprising breadth of moderately sized hydrophobic binding motifs (<40 nucleotides) available to natural nucleic acids. Studies of interactions with analogs indicate that two classes, four-way junctions and 4XG motifs, comprise receptors with shapes that prevent binding of specific steroid conjugates used in counter-selections. Furthermore, they strongly prefer nonhydroxylated steroid cores, which is typical for hydrophobic receptors. The third new class accommodates hydroxyl groups in high-affinity, high-selectivity binding pockets, thus reversing the preferences of the first two classes. The high-affinity binding of aptamers to targets efficiently inhibits double-helix formation in the presence of the complementary oligonucleotides. The high affinity of some of these receptors and tailored elimination of binding through counter-selections ensures that these new aptamers will enable clinical chemistry applications.

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Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups—Mannich phenols and general bases—that are capable of reactivating OPC-inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.

C1 and flexible analogs of (±)-nantenine were synthesized and evaluated for antagonist activity at human 5-HT 2A receptors in a calcium mobilization assay. This work has resulted in the identification of the most potent 5-HT 2A antagonist known based on an aporphine. Our results also suggest that the C1 position may be a key site for increasing 5-HT 2A antagonist activity in this compound series. In addition, the structural rigidity of the aporphine core appears to be required for nantenine to function as a 5-HT 2A antagonist.The monoamine neurotransmitter, serotonin (5-hydroxytryptamine, 5-HT, 1) is known to play a significant role in the central nervous system (CNS) modulation of appetite, mood, body temperature and sleep in humans. 1 There are fourteen serotonin receptors presently known, of which all except one (5-HT 3 ) are G-protein coupled receptors. 2 Ligands for the 5-HT 2A receptor are constantly being developed as chemical tools to study the functional role of this receptor in hallucinations, depression, anxiety and psychosis. 3-7 The role of 5-HT 2A receptor blockade in the neuropharmacological processes of addiction is also of growing interest. 8-13Aporphines are a diverse group of tetracyclic alkaloids found in several plant species and have been found to show a range of interesting biological activities such as antiplasmoidal, antihelminthic and antitumor activities. 14-18 As a result of their biological activities, new and facile synthetic methodologies to prepare these compounds are always being explored. 19,20 Others have reported the 5-HT 2A antagonist properties of the aporphine alkaloid nantenine (2). 21, 22 This pharmacodynamic property seems to be relevant to it's in vivo activity as an antagonist of the designer drug MDMA (methylenedioxymethamphetamine, "Ecstasy"). 23 Although aporphines have been evaluated as 5-HT 1A , α-adrenergic, and dopaminergic D1 and D2 ligands, very little SAR work has been performed on aporphines as 5-HT 2A antagonists. 21, 24-28 Part of our program is geared towards understanding the importance of selective receptor blockade as well as multi-potent antagonism involving 5-HT 2A receptors in the antagonism of MDMA-induced effects. Aporphines may be a valuable structural template for such a study, given the apparent promiscuity of these compounds across various CNS targets including 5-HT subtypes. As such, we have embarked on a study to evaluate the 5-HT 2APublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. antagonist activity of aporphines using 2 as a lead molecule. In this communication, we report results on the synth...