L-dopa-induced dyskinesias are a serious long-term side effect of dopamine replacement therapy for Parkinson’s disease for which there are few treatment options. Our previous studies showed that nicotine decreased L-dopa-induced abnormal involuntary movements (AIMs). Subsequent work with knockout mice demonstrated that α6β2* nicotinic receptors (nAChRs) play a key role. The present experiments were done to determine if α4β2* nAChRs are also involved in L-dopa-induced dyskinesias. To approach this, we took advantage of the finding that α6β2* nAChRs are predominantly present on striatal dopaminergic nerve terminals, while a significant population of α4β2* nAChRs are located on other neurons. Thus, a severe dopaminergic lesion would cause a major loss in α6β2*, but not α4β2* nAChRs. Experiments were therefore done in which rats were unilaterally lesioned with 6-hydroxydopamine, at a dose that lead to severe nigrostriatal damage. The dopamine transporter, a dopamine nerve terminal marker, was decreased by >99%. This lesion also decreased striatal α6β2* nAChRs by 97%, while α4β2* nAChRs were reduced by only 12% compared to control. A series of β2* nAChR compounds, including TC-2696, TI-10165, TC-8831, TC-10600 and sazetidine reduced L-dopa-induced AIMs in these rats by 23–32%. TC-2696, TI-10165, TC-8831 were also tested for parkinsonism, with no effect on this behavior. Tolerance did not develop with up to 3 months of treatment. Since α4a5β2 nAChRs are also predominantly on striatal dopamine terminals, these data suggest that drugs targeting α4β2 nAChRs may reduce L-dopa-induced dyskinesias in late stage Parkinson’s disease.

The rational design of molecular photonic devices relies on the ability to select components with predictable electronic structure, excited state lifetimes and redox chemistry. Electronic communication in multiporphyrin arrays depends critically on the relative energies and electron density distributions of the frontier molecular orbitals, especially the energetically close highest occupied molecular orbitals (a2u and a1u). To explore how these ground and excited state properties can be modulated, we have synthesized and characterized 40 free base ( Fb ), magnesium and zinc tetraarylporphyrins. The porphyrins bear meso-substituents with the following substitution patterns: (1) four identical substituents (phenyl, o-chlorophenyl, p-chlorophenyl, o,o'-difluorophenyl, pentafluorophenyl, mesityl); (2) one, two, three or four o,o'-dichlorophenyl substituents; (3) one p-ethynylphenyl group and three mesityl or pentafluorophenyl groups; (4) one p-ethynyl-o,o″-dichlorophenyl or p-ethynyl-o,o″-dimethylphenyl and three phenyl groups. For each neutral complex the ground state electronic properties were investigated using electrochemical methods and optical absorption spectroscopy. Similarly the absorption, emission, and relaxation properties of the lowest singlet excited state were probed by time-resolved absorption and fluorescence methods. Each oxidized complex was investigated by static absorption and liquid and frozen solution EPR spectroscopy. The collective results of these investigations have provided insights into the direct (orbital overlap) and indirect (inductive/conjugative) mechanisms by which halogenated phenyl rings influence the static and dynamic electronic properties of neutral and oxidized porphyrinic chromophores. Three key findings are as follows. (1) The effective electron-withdrawing strength of halogenated phenyl rings required to reverse the ordering of the a2u and a1u HOMOs in Mg versus Zn tetraarylporphyrins has been elucidated. (2) Appropriate halogenation can significantly increase the excited state lifetime of a Zn porphyrin relative to the unsubstituted complex. (3) Halogenation can be used to modulate redox potentials in a manner that complements the enhancement of other electronic properties. The insights gained from study of this library of porphyrins provide a foundation for tuning the electronic properties of monomeric porphyrins as building blocks for multichromophoric assemblies in optoelectronics and other applications.