Synthesis and structure-activity relationships of naphthamides as dopamine D₃ receptor ligands

A series of naphthamides were synthesized, and the affinities of these compounds were determined for dopamine D₂ and D₃ 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-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (7-12), (R)-N-(1-alkylpyrrolidin-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-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (26-31), and N-(9-alkyl-9-azabicyclo-[3.3.1]nonan-3β-yl)-4-bromo-1-methoxy-2- naphthamides (32, 33). The results of in vitro radioligand binding studies indicated that the majority of the naphthamide analogues bound with high affinity at both the D₂ and D₃ dopamine receptor subtypes and most of the compounds demonstrated some selectivity for the dopamine D₃ dopamine receptor subtype. These results demonstrated that both the structure of the central amine moiety (piperidine, pyrrolidine, and 9-azabicyclo[3.3.1]nonane) ring and the N-(alkyl) substitution on the amine significantly effects the binding affinity at D₂ and D₃ 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 D₃ receptors, or (c) decrease the affinity at D₂ receptors. The most potent analogue in this series was (S)-N-(1-cycloheptylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamide (10), which had equilibrium dissociation (K_i) values of 1.8 and 0.2 nM for D₂ and D₃ receptors, respectively. The most selective analogue was (R)-N-(1-cycloheptyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamide (30), which had K_i values of 62.8 and 2.4 nM for D₂ and D₃ receptors, respectively. Radioligand binding results for δ receptors indicated that the structure of the amine moiety and the N-(1-alkyl) substitutions also significantly influence the affinity and selectivity of these compounds at the δ₁ and δ₂ sigma receptor subtypes. The two naphthamides containing a 9-azabicyclo[3.3.1]nonan-3β-yl central ring were found to be selective for δ₂ receptors.