stepholidine and protoberberine

An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D(1), D(2) and serotonin 5-HT(1A) and 5-HT(2A) receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D(1) receptor with K(i) values of 50 and 6.3nM, while both compounds act as D(2) receptor antagonists (K(i)=305 and 145nM, respectively) and 5-HT(1A) receptor full agonists (K(i)=149 and 908nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT(1A) receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Berberine; Berberine Alkaloids; CHO Cells; Cricetinae; Cricetulus; Dopamine D2 Receptor Antagonists; HEK293 Cells; Humans; Microwaves; Motor Activity; Protein Binding; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Structure-Activity Relationship

The purpose of the present investigation was to clarify whether the hypotensive action of the protoberberine alkaloid, and dopamine receptor antagonist, (-)-stepholidine, can be ascribed to an effect on peripheral small arteries. For this purpose isolated mesenteric small arteries were suspended in microvascular myographs for isometric tension recording. Relaxations mediated by dopamine D1 receptors were antagonized by (-)-stepholidine. (-)-Stepholidine inhibited in a concentration-dependent manner the contractile responses evoked by noradrenaline (10(-6) M), but not the contractile responses evoked by depolarizing solution (KCl, 60 mM) or 9,11-dideoxy-11alpha,9alpha-epoxymethano prostaglandin F2alpha (U46619, 10(-7) M). Mechanical endothelial cell removal, blockade of K+ channels, muscarinic receptors or adrenoceptors did not influence the inhibitory effect of (-)-stepholidine on the contractile response evoked with noradrenaline in the segments. (-)-Stepholidine caused rightward shifts of the concentration-response curves for noradrenaline and phenylephrine. The pA2 values for (-)-stepholidine were 6.05 and 5.94 against noradrenaline and phenylephrine, respectively. Electrical field stimulation induced prazosin-sensitive frequency-dependent contractions in mesenteric small arteries. These contractions were significantly inhibited by 10(-6) and 10(-5) M (-)-stepholidine. In membranes from the rat cerebral cortex labelled with [3H]prazosin, (-)-stepholidine (10(-7)-10(-4) M) completely inhibited the specific binding of the ligand with a pKi of 5.6. The present investigation suggests the inhibitory effect of (-)-stepholidine on the alpha1-adrenoceptor-mediated contractions induced by exogenously added and nerve-released noradrenaline in peripheral small arteries might contribute to a hypotensive effect of the drug.

Topics: Animals; Berberine; Berberine Alkaloids; Calcium Channels; Dopamine Antagonists; Dose-Response Relationship, Drug; Electric Stimulation; In Vitro Techniques; Male; Mesenteric Arteries; Muscle Relaxation; Muscle, Smooth, Vascular; Norepinephrine; Potassium Channels; Rats; Rats, Wistar; Receptors, Adrenergic; Receptors, Muscarinic; Serotonin