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-3beta-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 sigma 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 sigma1 and sigma2 sigma receptor subtypes. The two naphthamides containing a 9-azabicyclo[3.3.1]nonan-3beta-yl central ring were found to be selective for sigma2 receptors.
Huang
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Department of Radiology-PET Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Luedtke
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Freeman
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RA
Wu
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Mach
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D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D017480:Receptors, sigma / Q000378:metabolism; D018411:Spodoptera / Q000166:cytology; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D008024:Ligands; D009281:Naphthalenes; D011758:Pyrroles; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C493595:Drd3 protein, rat; C427737:N-(1-cycloheptyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamide; C106107:sigma-2 receptor