General
Preferred name
dosulepin
Synonyms
Dosulepin hydrochloride ()
DOTHIEPIN ()
DOTHIEPIN HYDROCHLORIDE ()
Dothiepin hcl ()
Thaden ()
Prothiaden ()
Dothep ()
Ken-Pro ()
Dopress ()
Prepadine ()
Dothapax 75 ()
NSC-172130 ()
Dothapax 25 ()
Dothirpin ()
Dosulepin ()
Dothiepin ()
P&D ID
PD013128
CAS
25627-36-5
113-53-1
897-15-4
Tags
natural product
drug
available
First approval
1962
Drug Status
approved
Max Phase
Phase 4
Drug indication
Antidepressant
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
MOA
By binding to noradrenaline transporter (NAT) and serotonin transporter (SERT) in an equipotent manner and inhibiting the reuptake activity, dosulepin increases the free levels of noradrenaline and 5HT at the synaptic cleft. It is shown that the main metabolite northiaden is a more potent inhibitor of noradrenaline uptake than the parent drug [A19758]. ; ; Dosulepin displays affinity towards α2-adrenoceptors and to a lesser extent, α1-adrenoceptors [A6584]. Inhibition of presynaptic α2-adrenoceptors by dosulepin facilitates noradrenaline release and further potentiates the antidepressant effects [A19758]. It also downregulates central β-adrenoceptors by causing a decline in the number of receptors and reduces noradrenaline-induced cyclic AMP formation [L881, A19758]. ; Dosulepin binds to 5HT1A and 5HT2A receptors in the cerebral cortex and hippocampus as an antagonist. 5HT1A receptors are autoreceptors that inhibit 5HT release and 5HT2A receptors are Gi/Go-coupled receptors that reduces dopamine release upon activation [T28]. Antagonism at 5HT2A receptors may also improve sleep patterns. Dosulepin also binds to muscarinic acetylcholine receptors and causes antimuscarinic side effects such as dry mouth. By acting as an antagonist at histamine type 1 (H1) receptors, dosulepin mediates a sedative effect. ; ; Main metabolites northiaden, dothiepin sulphoxide and northiaden sulphoxide may also bind to 5HT, α2 and H1 receptors, although with less affinity compared to the parent drug [A19755].
TOXICITY
High mortality is associated with overdose of dosulepin (>5mg/kg) with the onset of toxicity occuring within 4-6 hours. Dosulepin may increase the risk of cardiovascular toxicity (cardiac arrhythmias, conduction disorders, cardiac failure and circulatory collapse) and severe hypotension, especially in the elderly [L881]. Withdrawal symptoms are reported in case of sudden cessation of therapy, which include insomnia, irritability, headache, nausea, giddiness, panic-anxiety, extreme motor restlessness and excessive perspiration. There have been reports of increased suicidal thoughts or behaviour with dosulepin treatment. Oral lowest published toxic dose (Toxic Dose Low, TDLo) is 90 mg/kg in infants and 4.5 mg/kg in female adults. Intravenous LD50 in mouse is 31 mg/kg [MSDS]. ; ; Most common adverse effects involve the central nervous system (drowsiness, extrapyramidal symptoms, tremor, confusional states, disorientation, dizziness, paraesthesia, alterations to EEG patterns), anticholinergic effects (dry mouth, sweating, urinary retention), cardiovascular system (hypotension, postural hypotension, tachycardia, palpitations, arrhythmias, conduction defects), endocrine system (altered libido), gastrointestinal system (nausea, vomiting, constipation) and blurred vision [L882]. ;
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Compound Sets
9
ChEMBL Approved Drugs
ChEMBL Drugs
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
JUMP-MOA Compound Set
Prestwick Chemical Library
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
34
Molecular Weight
295.14
Hydrogen Bond Acceptors
2
Hydrogen Bond Donors
0
Rotatable Bonds
3
Ring Count
3
Aromatic Ring Count
2
cLogP
4.68
TPSA
3.24
Fraction CSP3
0.26
Chiral centers
0.0
Largest ring
7.0
QED
0.81
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target
CHRM1, CHRM2, CHRM3, CHRM4, CHRM5, HRH1, SLC6A2, SLC6A4
MOA
norepinephrine reuptake inhibitor, serotonin–norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant
tricyclic antidepressant
Indication
depression
Source data
