Abstract
Employing the D(3) and D(4) selective methoxynaphthalines nafadotride and FAUC 182, respectively, as lead compounds, the pyrazolo[1,5-a]pyridine-3-carboxamides of type 1a and 2a as well as their 2-substituted regioisomers 1b and 2b were synthesized when following an ex-chiral pool approach. Dopamine receptor binding studies involving the target compounds (1a,b, 2a,b) and the respective optical antipodes ent-1a,b and ent-2a,b revealed the heterocyclic carboxamide 2a as a strong and selective D(4) ligand (K(i) = 8.6 nM). According to a mitogenesis assay, 2a shows D(4) partial agonist effects (29%, EC(50) = 6.7 nM) and, thus, might be of interest for the treatment of sexual dysfunction.
MeSH terms
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Animals
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Benzazepines / pharmacology
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Binding Sites
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CHO Cells
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Cricetinae
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacology*
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Humans
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Mutagenicity Tests / methods
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Naphthalenes / metabolism*
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Naphthalenes / pharmacology*
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology
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Quantitative Structure-Activity Relationship
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Rats
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Receptors, Dopamine / classification
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Receptors, Dopamine / drug effects*
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Sexual Dysfunctions, Psychological / drug therapy
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Spiperone / pharmacology
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Stereoisomerism*
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Sulpiride / pharmacology
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Swine
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Thymidine / pharmacology
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Tritium
Substances
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Benzazepines
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Heterocyclic Compounds
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Naphthalenes
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Pyrazoles
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Pyrrolidines
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Receptors, Dopamine
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Tritium
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Spiperone
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Sulpiride
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Thymidine