Synthesis and pharmacological evaluation of hydrophobic esters and ethers of butorphanol at opioid receptors.
We synthesized several hydrophobic esters and ethers of butorphanol and assessed their affinities at opioid receptors in CHO cell membranes. Tested compounds displayed moderate to high affinities to the mu and kappa receptors. The findings accord with previous evidence of a lipophilic binding pocket in the opioid receptors that can be accessed to afford good binding affinity without the need for a phenolic hydrogen-bond donor group. The most potent (K(i)=61 pM at mu and 48 pM at kappa) novel agent was (-)-N-cyclobutylmethylmorphinan-3-yl-14-ol phenoxyacetate (4d).
Fulton
Brian S
BS
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Knapp
Brian I
BI
Bidlack
Jean M
JM
Neumeyer
John L
JL
D000818:Animals; D002077:Butorphanol / Q000138:chemical synthesis* / Q000737:chemistry*; D016466:CHO Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008956:Models, Chemical; D009292:Narcotic Antagonists; D019800:Phenol; D011485:Protein Binding; D011957:Receptors, Opioid / Q000737:chemistry*; D013696:Temperature
D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D019800:Phenol; D002077:Butorphanol