31.1 Cholinocepter agonists(胆碱受体激动剂) Cholinergic receptor M-receptor Muscarine (毒蕈碱) -receptor Nicotine (烟碱)
3.1.1 Cholinocepter agonists(胆碱受体激动剂) Cholinergic receptor • M-receptor Muscarine (毒蕈碱) • N-receptor Nicotine (烟碱)
Cholinocepter agonists O NH O′NH Carbachol(卡巴胆碱) Bethanechol chloride(氯贝胆碱) HO o Muscarine N、 Acetylcholine
Cholinocepter agonists
SAR of Cholinocepter agonists Acyloxy group Quaternary ammonium H3CO-CH2-CH2+-N(CH3)Cl Ethylene group Ing's rule of five This rule suggests that there should be no more than five atom between the nitrogen and the terminal hydrogen atom for maximal muscarinic potency
SAR of Cholinocepter agonists Ing’s rule of five: This rule suggests that there should be no more than five atom between the nitrogen and the terminal hydrogen atom for maximal muscarinic potency
1. The molecule possesses a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt 2. For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of methyl group 3. The molecule should have an oxygen atom preferably an ester-like oxygen, capable of participating in a hydrogen bond 4. There should be a two-carbon unit between the oxygen atom and the nitrogen atom Acyloxy group Quaternary ammonium o H3co+cH2—cH2N(cH3)c Ethylene group
• 1. The molecule possesses a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt. • 2. For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of methyl group. • 3. The molecule should have an oxygen atom, preferably an ester-like oxygen, capable of participating in a hydrogen bond. • 4. There should be a two-carbon unit between the oxygen atom and the nitrogen atom
Me> h and bulky group R2=Me, decrease N-effect Triethyl substitution displays M-effect retains anticholinergic effect carbamoyl substitution is stable 2 R Et or ph substitution cation Is important lower activity R As( CH3)3, S(CH3)2 Se(Ch3)2 subtitution decrease the acitivity R3=Me, inhibit AChE N-effect> M-effect