Pathways

Metabolites of Dihydroergocornine are predicted with biotransformer.

Metabolites of Dihydroergocristine are predicted with biotransformer.

Alpha-dihydroergocryptine is usually referred to the mixture of the alpha and beta dihydroergocryptine. These two compounds are differentiated in the position of a methyl group. This structural difference is due to a proteinogenic amino acid replacement from leucine to isoleucine. Both compounds are hydrogenated ergot derivatives. Alpha-dihydroergocryptine approved drug product is as a part of an ergoloid mixture. Alpha-dihydroergocryptine has been studied for the early treatment of Parkinson disease as well as for its use in migraine prophylaxis, treatment of low blood pressure and peripheral vascular disorder.

Dihydroergotamine (DHE) is an ergot alkaloid used in the acute treatment of migraine headache and cluster headache. Dihydroergotamine is used as an abortive therapy for migraines with or without aura. Its use has largely been supplanted by triptans in current therapy due to the class's greater selectivity and more favourable side effect profile. DHE has several proposed mechanisms which may contribute to its therapeutic efficacy as an abortive therapy in migraines. Firstly, DHE's s agonist action on 5-hydroxytryptamine (5HT) 1b receptors in the smooth muscle of the cranial vasculature may provide relief via vasoconstriction of the blood vessels which typically become dilated due to the release of CGRP during migraine attacks. DHE's off-target action at alpha-adrenergic receptors may further contribute via this mechanism. The remaining mechanisms are thought to provide relief through the effects on the neurogenic causes of migraine symptoms. Agonist action by DHE on 5-HT1b and 5-HT1d receptors inhibits nociceptive signalling through the ventroposteromedial thalamus to the trigeminal sensory neurons. Further action on 5-HT1b and 5-HT1d receptors with the addition of agonist activity on 5-HT1f in the trigeminal nucleus caudalis decreases afferent signalling to trigeminal sensory neurons which contributes to central sensitization. The success of experimental compounds selectively targetting the 5-HT1f receptor lends support to this mechanism. Lastly, action at 5-HT1d receptors on trigeminal nerve terminals inhibits the release of vasoactive neuropeptides thought to contribute to pain and inflammation during a migraine attack. DHE is known to have 10-fold less potency at the 5-HT1b receptor than its predecessor ergotamine which reduces the incidence of vascular side effects. Notably, DHE slowly diffuses from receptors resulting in unreliable prediction of effects from plasma concentration.

Metabolites of Dihydroergotamine are predicted with biotransformer.

Dihydroetorphine binds to opioid receptors on presynaptic neuron membranes, stimulating the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and noradrenaline is inhibited. Opioids close N-type voltage-operated calcium channels and open calcium-dependent inwardly rectifying potassium channels. This results in hyperpolarization and reduced neuronal excitability. Morphine acts at A delta and C pain fibres in the dorsal horn of the spinal cord. By decreasing neurotransmitter action there is less pain transmittance into the spinal cord. This leads to less pain perception.

Dihydromorphine (also known as Paramorfan or Paramorphan) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of dihydromorphine acetate will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.

Dihydromorphine is a semisynthetic opioid analgesic. Dihydromorphine binds on pre-synaptic mu opioid receptors. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as GABA. Less GABA leads to disinhibition of dopamine cell firing in the spinal cord pain transmission neurons. This leads to less pain signaling and analgesia. Opioids close N-type voltage-operated calcium channels and open calcium-dependent inwardly rectifying potassium channels. This results in hyperpolarization and reduced neuronal excitability. The inhibition of A delta and C pain fibres in the dorsal horn of the spinal cord is very important as it slows the signaling of pain into the spinal cord.