Synthesis and structure-activity relationship of novel pyridyl ethers for the nicotinic acetylcholine receptor.

The preparation of novel pyridyl ethers as ligands for the nicotinic acetylcholine receptor (nAChR) is described. Varia- tions of the ring size of the azacycle and substitution on the pyridine had dramatic eAects on receptor binding aAnity with IC50 sa t the a4b2 nAChR ranging from 22 to >10,000 nM. The most potent molecule was (R)-2-chloro-3-(4-cyanophenyl)-5-((3-pyrrolidi- nyl)oxy)pyridine 27f with an IC50 of 22 nM. # 2000 Elsevier Science Ltd. All rights reserved. The discovery of compounds that can safely treat both acute and chronic pain without the side eAect of drug dependency would be an important advance in pain management. The discovery of epibatidine 1, a nAChR modulator, suggested that it might be possible to obtain an analgesic compound that is devoid of opioid-related side eAects. 1 But the narrow therapeutic index of epiba- tidine prohibited further development of the compound as an analgesic. 2 The discovery of ABT-594 fueled fur- ther investigation of the therapeutic potential of ligands that bind to the nAChR. 3 ABT-594 was shown to be at least 20 times more potent than morphine as an analgesic. 3a Furthermore, the initial findings suggested that the compound did not elicit the drug dependency associated with morphine. To this end, we now report the discovery of novel pyridyl ethers as potent ligands for the a4b2 nAChR subtype. Our program focused on using natural product ligands such as epibatidine 1 and nicotine 2 as starting points for analogue design as shown in Figure 1. We retained the pyridyl group as a part of the novel ligands. The only criteria left on the molecule was to place nitrogen in an optimal distance from the 3 position of the pyridine. Numerous models have been suggested in the literature regarding the location and angle of the nitrogen in respect to the pyridine. 4 As part of our structure-activity program, we identified the pyridyl ethers 3 as potent ligands that bound to the a4b2 nAChR subtype.