Glossary of med chem adrenergic neurotransmission
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- NE is the neurotransmittor of the?
- postganglionic sympanthetic neurons
interacts with pre & postsynaptic adrenergic receptors
- NE & Epi are released from?
- from adrenal medulla as neurohormones
also some from in neurons of CNS
- what is the basic structure of a catechol?
- benzene with 2 OH groups that are ortho to each other
- class of NE and Epi
state of NE & Epi at physiologic pH
- what is the difference between NE and Epi?
- nor - w/o methyl on N
- which enantiomer of the catecholamines has biological activity?
- R enantiomer
- a catechol will be oxidized into what?
- how do you stabilize catecholamine drugs?
- adding antioxidants such as ascorbic acid or sodium metabisulfite
- NE and Epi are synthesized from what aa?
- give the order of steps in the synthesis of epi from the beginning
- l-tyrosine -> L-DOPA -> dopamine -> NE -> Epi
- what inhibits tyrosine hydroxylase
- incr concen of epi, NE, DA
- which form of tyrosinehydroxylase is active?
- the phosphorylated form
- what is the methyl donor is the synthesis of epi from NE?
- s-adenosyl methionine
- when NE is released into the synaptic cleft, what 4 events can occur?
- it will stimulate effector cell
it can be taken up by adregergic neuron (stored or metabolized)
it can stimulate alpha2 receptors
it can diffusion into the general circulation
- how much of NE is taken back into the adreergic neuron by the uptake-1 system?
- the uptake-1 system can be inhibited by? what is the result of this?
- tricyclic antidepressants
more NE is left in the synaptic cleft - repeatedly stimulate adrenergic receptors
- what is the final molecule that results from the biotransformation of NE & Epi
- 3-methoxy-4-hydroxymandelic acid aka vanillyl mandelic acid
- what is pheochromocytoma?
- cancer of the adrenal medulla (more NE & Epi is produced, incr VMA)
- what is vanillyl mandelic acid a biomarker for?
- catecholamine turnover (incr VMA, incr turnover)
- both MAO and COMT occur in all tissues (ubiquitous), but what is the cellular location of each?
- MAO - outer membrane of mitochondria
COMT - cytoplasm
however, only MAO is present in neurons!
- what are the steps in the extraneuronal biotransformation of NE/Epi?
↝ 1. MAO 2. aldehyde dehydrogenase
- what are the steps that occur in the adrenergic neuron in the biotransformation of NE & Epi
- NE, Epi
- what are the 2 subtypes of adrenergic receptors
- alpha & beta
- what is the general structure of a adrenergic receptor?
- 7 transmembrane helical structure coupled to G-proteins
- what does the G-protein Gi do?
- inhibition of adenylyl cyclase
- what does the G-protein Gq do?
- stimulation of PLC
- what does the G-protein Gs do?
- activation of adenylyl cyclase
- alpha-1 adrenergic receptors are coupled to
- Gq proteins
- alpha-2 adrenergic receptors coupled to
- beta adrenergic receptors coupled to
- which receptors are post-synaptic receptors?
- what do the post-synaptic receptors do?
- mdiate organ/tissue responses of NE & Epi
- which receptor is pre-synaptic?
- what do the pre-synaptic receptors do?
- modulate the quantity of NE in the synaptic cleft
- give the aa that aid in binding NE to the receptor
- Ser 204
- how does Serine aid in the binding of NE to the receptor?
- provides hydrogen bonding with 2 OH groups (transmemembrane domain 5)
- how does Phenylalanine aid in the binding of NE to the receptor?
- hydrophobic interaction with phenyl ring
- how does Aspartate aid in the binding of NE to the receptor?
- ionic interaction (TMD 3)
- what is isoproterenol?
- a catechol that is not endogenous
- with regards to size, describe the alpha and beta adrenoceptors
- alpha - small space at receptor
beta - larger space, can accommodate bulky sidechains
- rank the binding affinity of the catechols to alpha adrenoceptors
- NE > Epi > Isoproterenol
- rank the binding affinity of the catechols to beta adrenoceptors
- isoproterenol > Epi > NE
- what is the difference bewteen beta-1 and beta-2 binding of Epi & NE
- beta-1 binds Epi & NE with the same affinity
beta-2 binds Epi more strongly than it does NE
- adrenoceptor subtype in the heart
- adrenoceptor subtype in the lungs
- adrenoceptor subtype in the arterioles & vascular smooth muscle
beta-2 (& alpha)
- adrenoceptor subtype in the eyes
- adrenoceptor subtype in the liver
- adrenoceptor subtype in the intestine
- adrenoceptor subtype in the kidney
- adrenoceptor subtype in the uterus
- response of the heart to adrenoceptor stimulation
- incr conduction velocity, force & rate of contraction (incr cardiac output)
- response of the lungs to adrenoceptor stimulation
- relax in tracheal & bronchial smooth muscles (bronchodilation)
- response of the arterioles & vascular smooth muscle to adrenoceptor stimulation (alpha-1)
- constriction of most peripheral vasculature (cerebral, cutaneous, mucous membrane, visceral)
- response of the arterioles & vascular smooth muscle to adrenoceptor stimulation (beta-2)
- dilation of skeletal muscle vasculature
- response of the eyes to adrenoceptor stimulation
- constriction of radial muscle (pupil dilation)
- response of the liver to adrenoceptor stimulation
- incr gluconeogenesis & glycogenolysis
- response of the intestine to adrenoceptor stimulation
- decr motility
- response of the kidney to adrenoceptor stimulation
- incr renin production
- response of the uterus to adrenoceptor stimulation (alpha-1)
- response of the uterus to adrenoceptor stimulation (beta-2)
- adrenoceptor subtype located in the adipocytes
- adrenoceptor subtype located in the CNS
- response of the adipocytes to adrenoceptor stimulation
- incr lipolysis
- response of the CNS to adrenoceptor stimulation
- reduced sympathetic outflow
- drugs that affect the biosynthesis of Epi & NE
- drugs that affect the storage of Epi and NE
- durgs that affect the release of Epi and NE
- what is the brand name for metyrosine?
- what is the brane name for reerpine?
- brane name for guanethidine
- brand name for guanadrel
- what is the MOA of metyrosine?
- it inhibits tyrosine hydroxylase, decr the biosynthesis of Epi and NE
- uses for metyrosine
- to manage pre-operative pheochromocytoma
- reserpine is isolated from what indian shrub?
- raulwofia serpentina
- MOA of reserpine
- inhibits transport of NE from cytoplasm into storage vehicles
- what is the onset of action of reserpine?
- works by depleting NE stores - takes time to diminish NE pool - slow onset
- what is the duration of action of reserpine?
- long lasting because there is no new NE being stored in the vesicles
- reserpine is used to treat
- severe hypertension
- MOA of guanethidine & guanadrel
- enter the neuron by uptake-1 process where they stabilizw the storage vesicle membrane to inhibit release of NE
- half life and bioavailability of guanethidine & guanadrel
half life: 5 days
half life: 12 hours
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