MedChem

What is the core of most opioids?

• phenanthrene system

  • core ABC rings

What helps hydromorphone bind to opioid receptors?

• ketone versus hydroxy vs morphine

  • better binding affinity

  • more lipophilic and better oral bioavailability

• alkyl group off the nitrogen required to bind to mu receptors

  • in vivo converted to NH+ for ionic interaction

What helps with buprenorphine bind to opioid receptors?

• cyclopropane and tert-butyl increase lipophilicity

  • very long in vivo half-life

  • more CNS and longer t ½

• tert-butyl increases binding to mu receptor

What helps with fentanyl bind to opioid receptors?

• much more lipophilic

  • get into CNS and bind in high concentration

• not rigid fused ring

  • able to bind to other areas of receptor

• very lipophilic

  • fast onset of action

• phenethyl and aniline rings provide additional interactions with mu receptors

  • phenethyl → hydrophobic interactions

  • aniline → pi-pi interactions

Why is duration of action so long in buprenorphine?

• large molecule undergoes slow dissociation and highly lipophilic

What helps with naloxone bind to opioid receptors?

• the long alykl chain (allylic) converts the molecule into antagonist

• will displace opioids in mu receptors

What helps with baclofen bind to receptors?

• synthetic derivative of neurotransmitter GABA

  • b/c GABA highly polar and cannot be used as drug due to poor absorption, fast elimination and cannot get into brain

  • R-enantiomer

• benzene makes it lipophilic, so can be used as drug

• chlorobenzene must be at beta position for pharmacologic activity

  • moving to alpha or gamma loses or weakens

What helps with cyclobenzaprine bind to receptors?

• dibenzocycloheptene derivative

• tert-butyl can bind to SE/NE

  • conversion by 2D6 NMe → selective binding to NE, less lipophilic and less side effects

• very lipophilic, highly into CNS

  • lots of side effects

What helps with tizanidine bind to receptors?

• benzothiadiazole derivative

• chlorine makes lipophilic and get into brain

• lots of drug-drug interactions due to 1A2 metabolism

What helps with lidocaine bind to receptors?

• need 2,6 dimethylbenzene conformation to be active

• binds to Na channels

• rapid first pass effect

  • lots of reactive metabolites

What is the most toxic metabolite of lidocaine?

can cause liver toxicity, allergic reaction and methemoglobinemia

What helps with capsaicin bind to receptors?

• sensitive to light due to double bond

• Trans vs Cis → equal binding affinity

• phenolic ring and methoxy group needed to bind