R ECE t a b r ~ JAN 0 5 1.995 1. SYNTHESIS AND 8ECEPTOR AFFINITIES OF NEW 3-QUINUCLIDINYL ALPHA-HETEROARYL-ALPHA-ARYL-ALPHA-HYDROXYACETATES (see Schemes in App. 1.1). Five analogues of 3-quinuclidinyl benzilate were prepared in which one phenyl ring was substituted by a heterocycle; a bromine was included on either the remaining phenyl or t h e heterocycle to provide information relating to the affinity of potential radiohalogenated derivatives. The required methyl 4-bromophenylglyoxalate (1) was synthesized from t h e reaction between 4-bromophenylmagnesium bromide with an excess of dimethyl oxalate a t-700 C. The reaction between ethyl oxalyl chloride with 2-bromothiphene provides ethyl 2-(5-bromothienyl)glyoxatate (2). Compounds (1) and (2) react with an equivalent amount of Grignard reagent to provide methyl or ethyl alpha-aryl-alpha-heteroarylglycolates (3). Transesterification of t h e methyl or ethyl esters (3) with (R,S)-3-quinuclidinol (4) in t h e presence of sodium metal provides t h e final products (5). A s a result of screening the novel compounds, we found a heterocyclic derivative of QNB that may surpass IQNB as a CNS receptor radioligand. This novel compound binds to mAChRs with an affinity that is greater than that of IQNB, i5 selective for the m l subtype, and is less lipophilic than IQNB, which should reduce t h e serum proteip binding relative to IQNB.[ [ [ (D I A LKY LA M I N 0) ALKYL]-1-PIPE RI D I N Y L] ACETYL]-1 0,l 1-D I HY D RO-5 H-D I B E N 20 [ b, e] [ 1,4] DIAZEPIN-1 1-ONES AS rn2-SELECTIVE ANTlMUSCARlNlCS (see Schemes in App. 1.2). The required 1 1-oxo-1 0,l 1-dihydro-5H-dibenzo[b,e] [1,4]diazepine (9) was prepared from the reaction between 2-chlorobenzoic acid and o-phenylenediamine. The reaction between 2-and 4-vinylpyridines (5 a , b) and dialkylamines (6a-e) provided 2-and 4-(dialkylamino)ethylpyridines (7). 4-Picolyllithium '(5~) reacted with 3-(dimethyl-or diethy1amino)propyl chloride to provide 4-[4-(dimethyl-or diethylamino) butyllpyridines (7). [(Dialkylamino)alkyl]pyridines-(7) were converted into the respective piperidines (8) by catalytic reduction(p1atinum oxide). Condensation of the tricycle (9) with chlocoacetyl chloride provided 5-(chloroacety1)-1 0,l 1-dihydro-SH-d i b e n z o [ b , e ] [ 1 , 4 ] d i a z e p i n-1 l-o n e (1 0). S u b s e q u e n t r e a c t i o n with [(dialkylamino)alkyl]piperidines (8) yielded t h e final products (4)-Compounds (4a-g,iIj) and two reference compounds (Table 111 in App. 1.2) were tested for their apparent affinities for the m l and m2 subtypes. Table 111 compares the selectivity and potency of these compounds to other compounds. These data demonstrate that (4j) is t h e most potent compound in the series. This compound is selective for m2 receptors over ml receptors by approximately 8-fold. These results also demonstrate t h a t (41) is approxhately 1 0 times more potent a t m2 receptors than AQ-RA 741. However, (4j) does not significantly penetrate the BBB. Cohen, Baumgold, Jin, de la Cruz, Rzeszotarski, Reba, J. Med. Chem. 36, ...