Exam 3 - Medical Chemistry Opioids Flashcards
Levo (-)
active for pain properties
Dextro (+)
inactive for pain properties
Number of Chiral centers morphine
5
How to tell Chiral center?
Substituted by 4 different groups
Rings of Morphine structure
4 six member rings, 1 aromatic ring
1 five member ring
Important groups for pharmacological activities
2 OH at 3,6 carbon
1 N + CH3
14 position carbon
Codeine into morphine
converted by CYP2D6 enzyme
12% of US pop has version that doesn’t allow this conversion to occur
Which form is Morphine usually in?
95% found in body is in protonated form
Ring “A” modification
Removing 3rd position OH will cause decrease in analgesic potency
Turning into CH3-O- will reduce analgesic potency but not as much as removing OH
Esterification and Etherification of OH (3 position)
Analgesic activity decreases
6-Acetylmorphine will be active but 3-Acetylmorphine will not (shows importance of 3-OH group)
Ring “C” modification
removal, etherification and esterification of 6-OH will give consistent increase in analgesic potency compared to morphine
6-OH group not essential for analgesic effects
Ring “D” modification, tertiary to quaternary
turning Tertiary amine into quaternary salt
inactive when admin peripherally but equi-active to morphine when admin directly into CNS
Morphinans structure
A,B,C,D ring plus N-CH3….Missing E (5 member w/ O)
Benzomorphans structure
A,B,D ring plus N-CH3
Piperidine structure
A and D ring plus N-CH3
Phenylpropyamines
Just A ring plus long chain and NH-CH3
Phenylpropyamines
Just A ring plus long chain and NH-CH3
Oripavin derivatives
More potent than thebaine due to OH at 3, instead of CH3-O
Etorphine and buprenorphine
Etorphine
Used for big animals, not humans
added bulk group with OH to 7 carbon
Buprenorphine
Partial agonist at mu receptor
more potent than morphine
Also has an added bulky group with OH to 7 carbon,
has tert-butyl
Morphine and codeine metabolism
Morphine-6-glucuronidide (M6G) is 2-4 times more potent than morphine
Morphine-3-glucuronidide (M3G) is not active
codeine can be turned into morphine and then M3G, or M6G
Morphine can also do OND to Normorphine which has decreased analgesic activity (Take CH3 off NH, turn into NH2+)
Morphinans
removing E ring, along with 6-OH and double bond will give you Levorphanol (L) or Dextromethorphan (D)
4-Anilidopiperidines
Amide bond is what gives it the “Anili” name.
Levorphanol
L form
8 times more potent than morphine as analgesic
Lipophilic and better oral/parenteral potency ration 2:1
4-Phenylpiperidines
only one marketed in USA is Meperidine
Its short acting analgesic, agonist at mu receptor
Undergoes N-demethylation to give Normeperidine which has little analgesic activity but significant toxicity
Meperidine Analogs
Diphenoxylate
Difenoxin
Loperamide
Dextromethorphan
D form
Inactive as analgesic but has antitussive potency
Diphenoxylate
low mu opioid agonist activity
high doses (40-60mg) cause euphoria and addiction
Used in combo with atropine to make diarrhea treatment
Difenoxin
used as antidiarrheal agent
made from Diphenoxylate via Easter hydrolysis.
5 times more potent after oral dosing, low CNS action and low abuse potential
Stays in CNS due to being Zwitterion
Loperamide
highly lipophilic and undergoes slow dissolution limiting its bioavailability to 40% of the dose
