FMI 14 - Modes of action of Valentonin and of 6–methoxy-harmalan FMI 14 - Modes of action of Valentonin and of 6–methoxy-harmalan
Clonidine and its analogues (antihypertensive α2 adrenergic receptor agonists 3. Action on dopaminergic D1 and D2 receptors
Dopaminergic agonists — such as ergoline derivatives (Lisuride, Bromocriptine, which cause drowsiness) are valentonergics (see figure 8).
etc.) and Quinagolide — used in the treatment of Parkinson’s disease are valentonergics HO (see figure 9). HO
HO Noradrenalin Serotonin H H N Dopamine N N H Dopamine H H H N H H HO HO N H HO H OH H HO N H N H3C N OMe HO N Cl N C N H H C Guanoxabenz C HO N O N N N N Moxonidine H N N Serotonin CH OH H Cl H H H 3 Lisuride H3C O N H N CH H C 3 Cl O N N O H O C Clonidine Cl C N C H N Rilmenidine O CH O N H 3 N H C Cl N C H C N N H N 3 O H CO H CH 3 H N 3 H H H H Metergoline Cl O C N H N Bromocriptine CH3 N H Valentonin N O H Guanfacine N C H N Br CH O H CH2 3 Cl H N N C N d d CH O C 3 H C H3CO 3 CH2 Valentonin N : Allosteric ligand N H CH3 N H
H3CO CH3 Figure 8: The chemical structures of Valentonin and noradrenergic agonists like Clonidine and its analogues α2 6-methoxy-harmalan N Lysergide (LSD) have common structural elements essential to the activation, via allosteric modulation, of noradrenergic α2 receptors H N (lower BP and HR) and serotonergic 5-HT receptors (hypnotic activity). 2C d H d Valentonin’s pharmacological actions provide an explanation not only of the here- : Allosteric ligand tofore unexplained action of Clonidine and its analogues on sympathetic tonus (lower BP and HR) used in the treatment of hypertension (noradrenergic agonist with CNS α2 Figure 9: The presence in Lisuride, Metergoline and Bromocriptine molecules of an allosteric ligand - a carbonyl C=O action) but also the drowsiness side effects of this class of medications (serotonergic group - explains why these antiparkinsonian and antiprolactin medications can activate, like VLT, dopaminergic D1/D2 5–HT2C receptors, even though the substituents on their tertiary amine (N) functional groups are too large. Of further note is that Lysergide (LSD), whose lysergic acid carbonyl (C=O) group has an unfavorable position and orientation for allosteric receptor agonists). modulation, cannot activate dopaminergic receptors, but rather blocks them.
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