Spiro-1-benzofuranpiperidinylalkanoic acids as a novel and selective sphingosine S1P receptor agonist chemotype.

The synthesis and SAR of a novel class of spirobenzofuranpiperidinyl-derived alkanoic acids 6-34 as sphingosine S1P receptor agonists are described. The target compounds generally elicit high S1P receptor agonistic potencies and in general are selective against both S1P and S1P receptor subtypes. The key compound 32 shows a high bioavailability of 73% and a CNS/plasma ratio of 0.

Grasping motor impairments in autism: not action planning but movement execution is deficient.

Different views on the origin of deficits in action chaining in autism spectrum disorders (ASD) have been posited, ranging from functional impairments in action planning to internal models supporting motor control. Thirty-one children and adolescents with ASD and twenty-nine matched controls participated in a two-choice reach-to-grasp paradigm wherein participants received cueing information indicating either the object location or the required manner of grasping. A similar advantage for location cueing over grip cueing was found in both groups.

7-Azaindole derivatives as potential partial nicotinic agonists.

We have investigated a series of 7-azaindoles as potential partial agonists of the alpha4beta2 nicotinic acetylcholine receptor (nAChR). Three series of 7-azaindole derivatives have been synthesized and evaluated for rat brain neuronal nicotinic receptor affinity and functional activity. Compound (+)-51 exhibited the most potent nAChR binding (Ki = 10 nM).

Design, synthesis and biological activity of rigid cannabinoid CB1 receptor antagonists.

The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated alpha, gamma-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pKi=7.

Study of the interaction between aryloxypropanolamines and Asn386 in helix VII of the human 5-hydroxytryptamine1A receptor.

We studied the stereoselective interaction between aryloxypropanolamines and the human 5-hydroxytryptamine1A (5-HT1A) receptor. R- and S-enantiomers of propranolol, penbutolol, and alprenolol were investigated for their ability to bind to human 5-HT1A wild-type and Asn386Val mutant receptors. Asn386 seemed to act as a chiral discriminator.