Lec. 10 Pharmaceutical Chemistry Past Paper PDF

University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ SYMPATHOMIMET...

University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ SYMPATHOMIMETIC AGENTS - Sympathomimetic agents produce effects resembling those produced by stimulation of the sympathetic nervous system. - They may be classified as agents that produce effects by a direct, indirect, or mixed mechanism of action depending on their chemical structures. - Direct-acting agents elicit a sympathomimetic response by interacting directly with adrenergic receptors. - Indirect-acting agents produce effects primarily by causing the release of NE from adrenergic nerve terminals; the NE that is released by the indirect-acting agent activates the receptors to produce the response. - Compounds with a mixed mechanism of action interact directly with adrenergic receptors and indirectly cause the release of NE. Direct-Acting Sympathomimetics Structure–Activity Relationships - The parent structure for many of the adrenergic drugs is β-phenylethylamine. - The manner in which β-phenylethylamine is substituted on the meta- and para- positions of the aromatic ring, on the amino (R1), and on α-, (R2)-, and β- positions of the ethylamine side chain influences not only their mechanism of action, the receptor selectivity, but also their absorption, oral activity, metabolism, degradation, and thus duration of action (DOA). - For the direct-acting sympathomimetic amines, maximal activity is seen in 1 University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ phenylethylamine derivatives containing (a) a catechol and (b) a (1R)-OH group on the β position of ethylamine portion of the molecule. - Optical Isomerism:  A critical factor in the interaction of adrenergic agonists with their receptors is stereoselectivity.  Substitution on either carbon-1 or carbon-2 yields optical isomers.  (1R,2S) isomers seem correct configuration for direct-acting activity. For CAs, the more potent enantiomer has the (1R) configuration. This enantiomer is typically several 100-fold more potent than the enantiomer with the (1S) configuration. - Separation of Aromatic Ring and Amino Group. The greatest adrenergic activity occurs when two carbon atoms separate the aromatic ring from the amino group. This rule applies, with few exceptions, to all types of activities. - R1, Substitution on the Amino Nitrogen Determines α- or β-Receptor Selectivity.  The amine is normally ionized at physiological pH. This is important for direct agonist activity, because replacing nitrogen with carbon results in a large decline in activity.  The number of substituents on the nitrogen also affects the activity. Primary and secondary amines have good adrenergic activity, whereas tertiary amines and quaternary ammonium salts do not. 2 University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬  The nature of the amino substituent also dramatically affects the receptor selectivity of the compound toward ARs and their subtypes. As the size of the nitrogen substituent increases, α-receptor agonist activity generally decreases and β-receptor agonist activity increases. Thus, NE has more α-activity than β-activity and E is a potent agonist at α-, β1-, and β2- receptors. ISO, however, is a potent β1- and β2-agonist but has little affinity for α-receptors. Also, it has been shown that N-tert-butyl group enhances β2-selectivity. For example, N-tert-butylnorepinephrine (Colterol) is 9 to 10 times more potent as an agonist at tracheal β2- receptors than at cardiac β1-receptors.  These results indicate that the β-receptor has a larger lipophilic binding pocket adjacent to the amine-binding aspartic acid residue than do the α- receptors.  Increasing the length of the alkyl chain offers no advantage, but if a polar functional group is placed at the end of the alkyl group, the situation changes. In particular, adding a phenol group to the end of a C2 alkyl chain results in a dramatic rise in activity by a factor of 800, indicating that an 3 University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ extra polar-binding region has been accessed, which can take part in H- bonding.  As R1 becomes larger than butyl group, it can provide compounds with α1- blocking activity (e.g., tamsulosin and labetalol).  Large substituents on the amino group also protect the amino group from undergoing oxidative deamination by MAO. - R2, Substitution on the α-Carbon (Carbon-2). Substitution by small alkyl group (e.g., CH3- or C2H5-) results in:  Slowing metabolism by monoaminooxidases (MAO) but has little overall effect on duration of action of catechols because they remain substrates for COMT. However, the resistance to MAO activity is more important in noncatechol indirect-acting phenylethylamines such as ephedrine or amphetamine.  Because addition of small alkyl group increases the resistance to metabolism and increases lipophilicity, such compounds often exhibit enhanced oral effectiveness and greater CNS activity than their counterparts that do not contain an α-alkyl group. 4 University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬  Methyl or ethyl substitution on the α-carbon of the ethylamine side chain reduces direct agonist activity at both α- and β-receptors.  α-Substitution also significantly affects receptor selectivity as follow:  An ethyl group in this position diminishes α-activity far more than β- activity, affording compounds with β-selectivity (e.g., ethylnorepinephrine and isoetharine).  In the case of β-receptors, for example, α-methyl or ethyl substitution results in compounds toward the β2-selectivity.  In the case of α-receptors, α-methyl substitution gives compounds toward the α2-selectivity. - OH substitution on the β-carbon (carbon-1)  Generally decreases CNS activity largely because it lowers lipid solubility.  Such substitution greatly enhances agonist activity at both α- and β- receptors. For example, ephedrine is less potent than methamphetamine as a central stimulant, but it is more powerful in dilating bronchioles and increasing blood pressure and heart rate.  Compounds lacking the β-OH group (e.g. Dopamine) have a greatly reduced adrenergic receptor activity. Some of the activity is retained, indicating that the OH group is important but not essential.  The R-enantiomer of NE is more active than the S-enantiomer, indicating that the secondary alcohol is involved in an H-bonding interaction. 5 University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ - Substitution on the Aromatic Ring.  Maximal α- and β-activity also depends on the presence of 3ʹ and 4ʹ OH groups by forming H-bonds between these catechol OH groups and the adrenoceptors.  Tyramine, which lacks two OH groups, has no affinity for adrenoceptors, indicating the importance of the OH groups.  Catechol moiety can be replaced with other substituted phenyl moieties to provide selective adrenergic agonists. For example, replacement of the catechol function of ISO with the resorcinol structure gives a selective β2- agonist, metaproterenol. Because β-agonists that contain this resorcinol ring is not a substrate for COMT, they tend to have better absorption characteristics and a longer DOA than their catechol-containing counterparts.  Replacement of the meta-OH of the catechol structure with a hydroxymethyl group gives agents, such as albuterol, which show selectivity to the β2- 6 University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ receptor. Because they are not catechols, these agents are not metabolized by COMT and thus show improved oral bioavailability and longer DOA.  It appears that the catechol moiety is more important for α2-activity than for α1-activity, therefore, removal of the p-OH group from E gives phenylephrine, which, in contrast to E, is selective for the α1-receptor. Phenylephrine is less potent than E at both α-and β-receptors, with complete absence of β2-activity.  The OH group can be replaced by other groups capable of interacting with the binding site by H-bonding. This is particularly true for the meta-OH group, which can be replaced by CH2OH, NHMe, NHCOR, NMe2, or NHSO2R group. 7 University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ 8