There is considerable interest in muscarinic acetylcholine receptor (mAChR) subtype selective agents as cholinomimetics for the treatment of senile dementia of the Alzheimer's type (SDAT). A series of substituted analogs similar to the musctinic agonists UHS and UH28 (analogs of the muscarinic agonist oxotremorine) were synthesized and evaluated pharmacologically. Several oxime analogues of UH5 demonstrate agonist-like properties in vitro at muscarinic receptors. One oxime in this series (Compound 18) was found to be almost five fold more ml selective than UH5. Although the involvement of several neurotransmitter systems has been implicated in Alzheimer's disease, the lOS8 of forebrain cholinergic function is a consistent neurobiological abnormality.4 Thus, cholinomimetics may hold promise as potential therapies for SDAT. Classical cholinomimetics are clinically ineffective due to peripheral parasympathetic effects, which are often observed at very low doses.Five sequenceunique muscarinic cholinergic receptor subtypes (mAChRs), ml through rns, have recently been identified.6 These subtypes have been so classified by the cloning and expression of five receptors containing unique amino acid sequences. These receptors mediate some of the actions of acetylcholine, mainly in tissues localized in the brain (ml, ms, and ms), and in the heart and gastrointestinal system (mz and m). The ml, m2 and ms receptors correlate pharmacologically to the M 1 (brain), M2 (heart) and Ma (glandular M2) receptors, respectively.7.s While selective antagonists have been developed for most of the subtypes, selective agonists have not been readily identified. Recently, UH5 and UH28 (analogs of the classical muscarinic agonist, oxotremorine) have been reported to be somewhat subtype selective muscarinic agonists.5 Efforts mported here are focused on the identification of muscarinic agonist analogs of UH5 and UH28 which may provide cholinomimetics with both a reduced liability for side effects (through subtype selectivity) and increased hydrolytic stability.Previous work in the muscarinic agonist area suggested that modification of the lactam in oxotremorine may protect the compound from enzymatic oxidation and maintain agonist activity.9.10 We anticipated that opening the lactam ring and replacing the amide nitrogen with a carbon atom might also enhance in viva stability. Bradburytt optimized the tertiary amine region of these molecules. Combining these functional optimizations, we synthesized a series of ketone and oxime analogs of UH5 and UH28.