Docking the tails: The triggering of a single cleavage at the core of a new class of dendrimers (see, for example, the second generation dendron) results in a spontaneous chain fragmentation and the release all of the tail (reporter) units. Such dendrimers may be applied as a general platform for prodrugs or sensor molecules for enzymatic activity.

"Chemical adaptor systems" are molecules used to link different functionalities, based on unique reactivity that allows controlled fragmentation. Two different mechanistic reactivities were used to prepare chemical adaptor systems. The first is based on a spontaneous intra-cyclization reaction to form a stable ring molecule. Cleavage of the trigger generates a free nucleophile, for example, an amine group, which undergoes intra-cyclization to release the target molecule from the handle part (e.g., a targeting antibody or a solid support for synthesis). The second applied reactivity is an elimination reaction, which is usually based on a quinone-methide-type rearrangement. Similarly, cleavage of the trigger generates a free phenol functionality, which can undergo a self-elimination reaction through a quinone-methide rearrangement to release the target molecule. The adaptor molecules have been applied in the field of drug delivery to release a drug from a targeting device and in the field of solid-phase synthesis to release a synthetic molecule from the solid support. A chemical adaptor molecule has also been used as a building unit to construct dendrimers with a triggered fragmentation.

2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA, 4) is a cyclic analogue of the antiepileptic drug (AED) valproic acid (VPA) (1). alpha-F, alpha-Cl, alpha-Br, and alpha-methyl derivatives of 4 and their amides were synthesized and tested in rodent models for anticonvulsant potency and AED-induced teratogenicity. In the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol (scMet) tests, alpha-Cl-TMCD (17) had ED(50) values of 97 and 27 mg/kg, respectively. alpha-F-TMCD (11) was 120 times more potent than VPA in the rat-scMet test (ED(50) = 6 mg/kg) and had a protective index (PI = TD(50)/ED(50)) of 20. In the 6 Hz psychomotor mouse model 11 had ED(50) values of 57 mg/kg (32 mA) and 59 mg/kg (44 mA). The ED(50) values of 11 in the hippocampal-kindled rat model and in the pilocarpine-induced-status rat model were 30 and 23 mg/kg, respectively. Unlike 1, 11 was nonteratogenic in mice. This novel compound has the potential to become a candidate for development as a new potent and safe antiepileptic and CNS drug.

Valproic acid (VPA) is an effective antiepileptic drug with an additional activity for the treatment of bipolar disorder. It has been assumed that both activities arise from a common target. At the molecular level, VPA targets a number of distinct proteins that are involved in signal transduction. VPA inhibition of inositol synthase reduces the cellular concentration of myo-inositol, an effect common to the mood stabilizers lithium and carbamazepine. VPA inhibition of histone deacetylases activates Wnt signaling via elevated ␤-catenin expression and causes teratogenicity. Given the VPA chemical structure, it may be possible to design VPA derivatives and analogs that modulate specific protein targets but leave the others unaffected. Indeed, it has been shown that some nonteratogenic VPA derivatives retain antiepileptic and inositol signaling effects. In this study, we describe a further set of VPA analogs and derivatives that separate anticonvulsant activity from effects on neuronal growth cone morphology. Lithium, carbamazepine, and VPA induce inositol-dependent spread of neuronal growth cones, providing a cell-based assay that correlates with mood-stabilizing activity. We find that two constitutional isomers of VPA, propylisopropylacetic acid and diisopropylacetic acid, but not their corresponding amides, and N-methyl-2,2,3,3-tetramethyl-cyclopropanecarboaxamide are more effective than VPA in increasing growth cone spreading. We show that these effects are associated with inositol depletion, and not changes in ␤-catenin-mediated Wnt signaling. These results suggest a route to a new generation of central nervous system-active VPA analogs that specifically target bipolar disorder.

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