Hao Bai

Structure-activity studies related to ABT-594, a potent nonopioid analgesic agent: Effect of pyridine and azetidine ring substitutions on nicotinic acetylcholine receptor binding affinity and analgesic activity in mice

Analogs of A-98593 (1) and its enantiomer ABT-594 (2) with diverse substituents on the pyridine ring were prepared and tested for affinity to nicotinic acetylcholine receptor binding sites in rat brain and for analgesic activity in the mouse hot plate assay. Numerous types of modifications were consistent with high affinity for [3H]cytisine binding sites. By contrast, only selected modifications resulted in retention of analgesic potency in the same range as 1 and 2. Analogs of 2 with one or two methyl substituents at the 3-position of the azetidine ring also were prepared and found to be substantially less active in both assays.

Synthesis and structure-activity relationships of pyridine-modified analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, A-84543, a potent nicotinic acetylcholine receptor agonist

Analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, (A-84543, 1) with 2-, 4-, 5-, and 6-substituents on the pyridine ring were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 9,000 nM when tested in vitro for neuronal nicotinic acetylcholine receptor binding activity. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors indicates that pyridine substitution can have a profound effect on efficacy at these subtypes, and several subtype-selective agonists and antagonists have been identified.

Efficient asymmetric synthesis of ABT-594; a potent, orally effective analgesic

Abstract A concise asymmetric synthesis of ( R )-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594) is presented in which the key intermediate t -butoxycarbonyl protected (2 R )-azetidinylalcohol is obtained in three steps from the dibenzyl ester of D-aspartic acid in 44% yield and >99% ee.

Titanium Tetraisopropoxide Catalyzed Synthesis of Base‐Sensitive Cyanoguanidine Analogs

Abstract The synthesis of base‐sensitive cyanoguanidine analogs of potent potassium channel openers was accomplished in two steps by converting the thiourea to a carbodiimide followed by Ti(OiPr)4 catalyzed addition of cyanamide in dichloromethane.

AMINO ACID-DERIVED PIPERIDIDES AS NOVEL CCKB LIGANDS WITH ANXIOLYTIC-LIKE PROPERTIES

Abstract The development of a novel series of carbamoylamino acid benzoylpiperidides as CCK B ligands is described. Selected members of the series antagonized CCK 8 -induced calcium mobilization and showed efficacy in the mouse elevated-plus maze, a measure of potential anxiolytic activity.