1. 3',4'- dihydroxy substitued benzene ring provides excellent receptor activity for both α and β sites.
2. However, there is poor oral bioavailablity due to COMT.
3. 3',5'-dihydroxy compounds are not good substrates for COMT. Also 3',5'-dihydroxy compounds are more selective for β2- receptors.
4. albuterol has
3'-hydroxymethyl (i.e. 3-CH2OH) and 4'-OH = β2 selective.
5. 3'-amino or even
3'-formylamino are also resistant to COMT.
6. Basically atleast one group must be capable of forming hydrogen bonds. And if only one group present it should be at 4'-position (then β activity is retained) e.g. Ritodrine - has only one 4'-OH, yet it has good β-activity. Also since Ritodrine has a large N-substituent = β2 selectivity is higher, therefore used in premature labor to relax the uterus.
7. If only a 3'-OH or a 3'-Sulfonamide present = lowered α activity but eliminates β activity. Therefore selective α-agonists can be made e.g. phenylephrine and metaraminol.
8. α-receptors accept a wide range of tolerance for agonist activity e.g. 2',5'-dimethoxy substitution of methoxamine which is an α-receptor agonist but also a β-blocker at higher concentrations.
9. Phenylephrine, metaraminol and methoxamine are all agents which cause vasoconstriction.
10. When R3 = H - has both direct and indirect. (indirect activity is of two kinds - either by displacement of the neurotransmitter from the cell, or by inhibition reuptake of the neurotransmitter)
1. By default must be present at β position to primary amine (i.e. spaced 2 carbons away).
2. being a chiral center the 1 position must be in R configuration for maximum activity (but many drugs sold as racemic i.e. R/S mixture)- exception dobutamine.
1. small alkyl groups such as methyl and ethyl slows down metabolism by mono-amine oxidases (MAO). However they are still substrates for COMT.
2. Resistance to MAO more important for non-catechol, indirect acting phenyl ethyl amines.
3. When methyl substituent changed to ethyl = there is increased β selectivity over α.
4. Substitution at position 2 causes formation of diastereomer which have a wide variety of activity.e.g. α-methyl norepinephrine erythro i.e. 1R, 2S = maximal direct activity. Position 2 has great influence as the 1R,2R diastereomer of α-methyl norepinephrine has primarily indirect activity, even though the hydroxy containing C1 is in the same orientation as epinephrine/norepinephrine.
5. The direct acting α-methyl norepinephrine, due to the methyl group is agonist for α2>α1 receptor. (This is important for antihypertensive action of α-methyl dopa).
6. The same stereochemical relationship holds true for metaraminol & other phenylethanolamines where stereochemistry is investigated.
|The pKa of the amine is approximately 8.5-10. This makes it basic and positively charged at physiological pH
Properties of R1 Substituent on amino nitrogen:
1. as the size increases - selectivity for β receptor increases over α receptors.
2. α and β activity is maximum when R1= methyl (e.g. epinephrine).
3. R1= isopropyl (e.g. isoproterenol) - α activity is negligible and only β activity present.
4. This observation assumes that β receptors have a large lipophilic binding pocket adjacent to the amine binding aspartic acid.
5. When R1> t-butyl (e.g. into aryl-α-methyl alkyl groups) = α1 affinity present but no intrinsic activity (e.g. labetalol). Therefore useful for blockers.
6. t-butyl group = β2 selectivity (e.g. colterol, terbutaline, albuterol)
7. aryl-alkyl group where alkyl chain ranges from 2-11 carbons or oxygen atoms = β selectivity with increased lipophilicity & cell penetration for longer duration of action e.g. Salmeterol & Formeterol are β selective and more so β2 selective.
|11. Since Norepinephrine stimulates both α and β adrenoceptors, indirect activity cannot be selective.
||7. Stereochemistry also plays an important role in determining direct or indirect activity. e.g. Ephedrine (-) i.e. 1R,2S = mixed α and β direct activity.
Ephedrine (+) i.e. 1S,2R = primarily indirect activity.
Pseudoephedrine i.e. 1S,2S = primarily indirect activity with negligible direct activity.