Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pKi values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pKi 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 microgram/kg i.v.), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.

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The Pauson−Khand reaction of cyclobutenes 3−5 with a variety of acetylenes yielded cis-anti cis-tricyclo[5.3.0.02,6]decanes 9−17. The unwanted regioisomers 9a and 10a were the sole products using acetylene, but there was a remarkable reversal in orientation of the cyclobutene component yielding the desired regioisomer 13b upon using (trimethylsilyl)acetylene. The importance of the allylic methyl group in the cyclobutenes in directing the regiochemical outcome was substantiated by the lack of selectivity in Pauson−Khand reactions of desmethylcyclobutene 5 with acetylene and (trimethylsilyl)acetylene. The relative unimportance of electronic control of regiochemistry was concluded from the consistent ratio of Pauson−Khand reaction products from norbornenone 22 with various acetylenes. A hypothesis rationalizing the regiochemical outcome was based on steric interactions of the allylic methyl group from the cyclobutene component with either the smaller acetylene substituent or the CO ligands on the cobalt. This steric interaction was further hypothesized to be influenced by the larger acetylene substituent sterically crowding the CO ligands on the cobalt.

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