Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M1 agonists.

The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.

A Pilot Study of Aerobic Exercise as an Adjunctive Treatment for Drug Dependence.

Intervention to increase exercise in drug dependent patients represents a potentially useful yet unexplored strategy for preventing relapse. However, there are currently no established exercise interventions for use with this population. The purpose of this pilot study was to examine the feasibility of aerobic exercise as an adjunct to substance abuse treatment among drug dependent patients. Participants included 16 (31% female, 38.3 years old) drug dependent patients who participated in a 12-week, moderate-intensity aerobic exercise intervention. Participants attended a mean of 8.6 sessions (out of 12). Participants demonstrated a significant increase in percent days abstinent for both alcohol and drugs at the end of treatment, and those who attended at least 75% of the exercise sessions had significantly better substance use outcomes than those who did not. In addition, participants showed a significant increase in their cardiorespiratory fitness by the end of treatment. While preliminary, this study is one of the first to demonstrate the feasibility of incorporating aerobic exercise during drug abuse treatment. Future randomized control trials are a necessary next step to test the efficacy of a moderate-intensity aerobic exercise intervention as an adjunct to drug abuse treatment in this patient population.