Tetrahydropapaveroline (THP), a "mammalian alkaloid" endogenously formed in mammals and a urinary excretion product of parkinsonian patients treated with dopa, its optical isomers (la, lb), and related compounds (including (*)-trimetoquinol, (*)-/(-)-/(+)-N-norreticulines, 6'-Br-THP, papaveroline, norlaudanosine, and polycyclic isoquinolines) were synthesized and studied to explore their interactions with α-adrenergic, β-adrenergic, and dopaminergic receptors, as well as antinociceptive activity. Receptor binding assays used [³H]dihydroalprenolol (β-adrenergic), [³H]spiroperidol (dopaminergic), and [³H]WB-4101 (α-adrenergic) in rat cerebral cortex or striatum. The hot-plate antinociceptive assay evaluated norreticulines. Results showed (*)-trimetoquinol was among the most potent in inhibiting β-adrenergic receptor binding (Ki = 0.1 μM). 6'-Br-THP was more potent than dopamine in the α-adrenergic assay (Ki = 0.5 μM vs dopamine's 1.25 μM) and equipotent in the dopaminergic assay (Ki = 1.5 μM vs dopamine's 1.25 μM). Stereospecificity was observed: THP's S-isomer (la) was ~100-fold more active than the R-isomer (lb) in β-adrenergic binding; (-)-norreticuline (3a) was ~25-fold more effective than (+)-norreticuline (3b) in β-adrenergic assay and had antinociceptive activity (ED₅₀ = 9.9 μmol/kg, ~1/3 the potency of morphine). Active compounds were conformationally mobile secondary amines, while conformationally inflexible molecules (e.g., aromatic isoquinolines, polycyclic compounds) were inactive. These findings highlight the roles of stereochemistry, conformational flexibility, and secondary amine structure in receptor interactions and biological activity of THP-related compounds.