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7586 Week 1 Objectives (Abdelaziz)
Terms in this set (9)
Relate the structural variations of ureides to its antiepileptic effects.
- Many of the standard anticonvulsants contain the ureide structure. Small changes in the X substituent can cause significant changes in the types of seizures controlled.
- Ring N (hydantoins) switching to ring O (oxazolidinediones) or ring CH2 (succinimides) result in switching from effectiveness against partial and generalized tonic-clonic seizures to effectiveness against absence seizures.
Detect the other indications for barbiturates and benzodiazepines.
- Many barbiturates display sedative-hypnotic activity.
- Paradoxically, many barbiturates cause convulsions at larger doses!
- The mechanism of antiseizure action for the barbiturates is unknown.
- The ones useful for epilepsy are: phenobarbital, mephobarbital, and primidone.
- Slow onset of action - administered after benzodiazepeines for the treatment of status epilepticus.
Explain the good bioavailability of midazolam and only the small doses of gabapentin.
- Midazolam is particularly useful for treating status epilepticus because of its diazepine ring, which opens at a low pH, allowing it to be dissolved in aqueous solution for IM injection.
- The ring closes at physiologic pH, increasing lipophilicity with rapid IM absorption, brain penetration, and fast onset of action.
- The bioavailability of gabapentin is favorable when given in low doses and somewhat less at high doses because of saturable intestinal uptake by the l-amino acid transporter.
- This transporter is very susceptible to substrate saturation.
- Gabapentin absorption and distribution into the CNS appear to be dependent on this transporter.
- NOTE: Gabapentin has no direct GABA-mimetic activity. Instead, it binds allosterically to the P/Q-type calcium channels, decreasing their activity.
Describe the structure of endogenous opioid peptides, their SAR and their structural similarity to morphine.
- Opioid receptors are thought to be activated by endogenous peptides under physiologic conditions.
- The Tyr1 at the first amino acid residue position of all the endogenous opioid peptides is essential for activity (removal of the phenolic hydroxyl group or the base nitrogen will abolish activity; the Tyr1 free amino group may be alkylated with methyl or allyl groups to give agonists and antagonists, but it must retain its basic character).
- The next most important moiety is the phenyl group of the Phe4 (removal of this group or changing its distance from Tyr1 results in full or substantial loss in activity).
Identify the structural features important for the binding of morphine and other opioids to their target receptor(s).
- The first four amino acids (Tyr-Gly-Gly-Phe) are essential for peptide ligands to bind to and activate all opioid receptor types.
- The N-terminus amino acids can then be referred to as carrying the "message" to the receptors.
- Adding additional amino acids to the C-terminus can "address" the message to a specific receptor type.
- The additional peptide chain may be affecting the address (selectivity) by providing new and favorable binding interactions to one of the receptor types.
Explain the rationale of modifying morphine to design prodrugs such as codeine and heroin.
- Classical morphine analogues contain the characteristic phenanthrene ring system (three fused rings A, B, and C).
- As a weak base, morphine exists in equilibrium of ionized and unionized forms (the unionized form crosses the BBB and re-establishes equilibrium upon entry; the ionized form binds to the receptors).
- The phenol ring Is required for binding. 3-hydroxyl etherification reduces opioid potency by about 10-fold due to less binding but increases oral absorption and makes them more resistant to metabolism (codeine).
Compare the SAR of opioid agonists and antagonists.
- An N17 amino nitrogen is an essential feature of all opioids (permits receptor anchoring with Asp residue)
- Substitution at 17-N in morphine is very sensitive and causes wide variations.
o N-demethylation loses 75% of activity (normorphine)
o N-oxide is inactive
- Quaternary amine is required for binding.
o allyl or cyclopropyl is an antagonist (nalorphine and naltrexone)
o naloxone is orally inactive due to rapid metabolism by oxidation
- Phenol ring is required for binding.
o 3-hydroxyl etherification reduces opioid potency by about 10-fold but increases oral absorption. Ethers are also more resistant to metabolism (codeine).
- Further oxidation of 6-hydroxyl OR changing 14-H to hydroxyl increases potency 6 to 10-fold (hydromorphone and oxymorphone).
- Opioid receptors are highly stereoselective for the levorotary (-) isomers of morphine-like ligands. The dextrorotary (+) isomers do not bind well to these receptors.
- Structure simplification led to synthetic analogues like fentanyl (50 to 100 times morphine activity) with more rapid onset and shorter duration.
List examples of opioids designed with lower analgesic activity but better pharmacokinetic properties such as oral bioavailability, metabolic stability, and ability to cross the BBB.
- favorable oral bioavailability
- metabolic stability
- ability to cross BBB
Identify the mode of action of dual-acting agents (e.g., Tramadol).
Orally active Tramadol has a dual mechanism of action: μ-receptor stimulation and inhibition of NE or 5-HT reuptake in the CNS.
- Tramadol 1S, 2S-(-) isomer inhibits NE reuptake
- Tramadol 1R, 2R-(+) isomer inhibits 5-HT reuptake
- the dextrorotary isomer of the O-dealkylated metabolite stimulates μ-opioid receptors to produce analgesia
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