Synthesis and structure-activity relationships of naphthamides as dopamineD-3 receptor ligands

A series of naphthamides were synthesized, and the affinities of these comp ounds were determined for dopamine D-2 and D-3 receptors using radioligand binding techniques. The naphthamide compounds that were prepared include N- (1-alkylpiperidin-4-yl)-4-bromo-1-methoxy-2-naphthamides (1-6), (S)-N-(1-al kylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (7-12), (R)-N-(1-alkyl pyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (13-18), (S)-N-(1-alkyl-2 -pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (19 -25), (R)-N-(1-al kyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (26-31), and N-( 9-alkyl-9-azabicyclo-[3.3.1]nonan-3 beta -yl)-4- bromo-1-methoxy-2-naphtham ides (32, 33). The results of in vitro radioligand binding studies indicate d that the majority of the naphthamide analogues bound with high affinity a t both the D-2 and D-3 dopamine receptor subtypes and most of the compounds demonstrated some selectivity for the dopamine D-3 dopamine receptor subty pe. These results demonstrated that both the structure of the central amine moiety (piperidine, pyrrolidine, and 9-azabicyclo[3.3.1]nonane) ring and t he N-(alkyl) substitution on the amine significantly effects the binding af finity at D-2 and D-3 dopamine receptors. The bulkiness of the N-(1-alkyl) substituent was found to (a) have no effect on pharmacologic selectivity, ( b) increase the affinity at Ds receptors, or (c) decrease the affinity at D -2 receptors. The most potent analogue in this series was (S)-N-(1-cyclohep tylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamide (10), which had equilib rium dissociation (K-i) values of 1.8 and 0.2 nM for D-2 and D-3 receptors, respectively. The most selective analogue was (R)-N-(1-cycloheptyl-2-pyrro lidinylmethyl)-4-bromo-1-methoxy-2-naphthamide (30), which had K-i values o f 62.8 and 2.4 nM for D-2 and D-3 receptors, respectively. Radioligand bind ing results for sigma receptors indicated that the structure of the amine m oiety and the N-(l-alkyl) substitutions also significantly influence the af finity and selectivity of these compounds at the sigma (1) and sigma (2) si gma receptor subtypes. The two naphthamides containing a 9-azabicyclo[3.3.1 ]nonan-3 beta -yl central ring were found to be selective for sigma (2) rec eptors.