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Information about chiral

Published on April 22, 2008

Author: Taddeo


Slide1:  Stereoisomers: Adding further complication to the simple idea of nasal decongestion Gareth Lim Pharmac 4AA3 March 4th , 2004 Slide2:  Agenda Uses of ephedrine (EPH) and pseudoephedrine (PDE) Origins Some facts and statistics on use Structures Stereoisomers Nomenclature Definitions Implications to drug actions Mechanisms of action of nasal decongestants Where they act in the body Signal transduction pathways Concluding remarks What can be learned from this? Recommended readings Slide3:  Why do people take Ephedrine? Appetite suppression Weight-loss Metabolic enhancement Body-building effects Euphoria Increase energy/wakefulness Vasopressor Decongestant Bronchodilator for asthma Slide4:  Origins of ephedrine and pseudoephedrine Ephedra is a species of plants from which both ephedrine and pseudoephedrine are derived from Chemical derivatives from Ephedra sinica (Ma Huang) have caused much controversy Ephedrine (1924) is one derivative from Ma Huang that is used for a variety of effects Following discovery of ephedrine (EPH), pseudoephedrine (PDE) was discovered Slide5:  Due to similar effects of EPH and PDE, both are listed on the banned substance lists by the International Olympic Committee Strict regulations are set by Health Canada for drugs containing ephedrine “Natural” or “Herbal” products may contain ephedrine Similarly, sales of products containing pseudoephedrine are difficult to estimate because of the large volume of OTC products that are sold Statistics and general information Slide6:  Are these two compounds the same drug? Ephedrine Pseudoephedrine Chemical and structural information on EPH and PDE CAN THESE CHIRAL CENTERS AFFECT THE ACTION OF THE DRUGS? Slide7:  Background Information on chirality Slide8:  More terminology…. Isomer Constitutional Isomer Stereoisomers Enantiomers Diastereomers (Nat Rev Drug Dis, 2002, 1: 753) Slide9:  Relationship between stereostructure and pharmacological activity Stereoisomers are possible when there is a chiral center to the molecule Slide10:  Nomenclature Designated as dextrorotatory, D-,d-, or (+) because molecules rotate plane polarized light to the right Designated as levorotatory, L-,l-, or (-) because molecules rotate plane polarized light to the left Cahn-Ingold-Prelog method is used to determine absolute configuration R (rectus) or S (sinister) Ranking based on atomic number There is no relationship between absolute configuration and optical activity (Ann Med, 2002, 34: 537) Slide11:  Eutomer vs Distomer (Ann Med, 2002, 34: 537) Racemic mixtures: mixtures containing BOTH enantiomers When racemic mixtures are used, complications arise: Association of adverse events with one enantiomers Differences in enantiomers pharmacokinetics Stereoselective metabolism Effects of one enantiomer on the PK of the other Enantioselective drug-drug interactions Racemic mixtures-- Information Slide12:  Why is chirality so important? (Annu Rev Pharmacol, 1970, 10: 51 ) Slide13:  Easson & Stedman hypothesis (1933) Sequence of 3 key receptor elements and 3 substituents attached to asymmetric carbon center are complementary If complementary aligned isn’t present, leads to inactivity or lesser activity (Biochem J, 1933, 27:1257) Slide14:  Structure and pharmacological activity The favorable isomer is due to steric interactions between substituents at each chiral center In diastereomeric drugs, potency differences may arise because the more active diastereomer has a greater capability of achieving a pharmacophoric conformation It is difficult to predict which diastereomeric conformation is more favorable without performing actual experiments because of the possibility of the receptor having different conformations as well If enantiomers do not differ in activity, chiral center must be located in a region that does not interact with the receptor (Trends Pharmacol Sci, 1993, 14:68) (Annu Rev Pharmacol, 1970,10: 51) Slide15:  What else can chirality cause? Slide16:  Sometimes, chiral centers actually have no impact on the potency of a drug CH3CH2C- CH3CH2C- CH3CH2C- CH3 CH3 CH3 H H CH3 (J Med Chem, 1986, 29: 849) Lovastatin Slide17:  Enantiomers may have completely opposite effects WHY??? (Life Sci, 2001, 68: 2227) Slide18:  When the (±) TAN-67 was separated into (+) and (-) compounds…. Slide19:  Can stereoisomers be harmful? One classic example is thalidomide (Eur J Clin Pharmacol, 2001, 57: 365) Has a chiral center and is found to be a 1:1 racemic mixture R-isomer was associated with sedative effects S-isomer is now hypothesized to be the cause of birth defects Slide20:  Chiral inversions as seen with thalidomide are not that uncommon (Br J Clin Pharmacol, 1985, 19: 669) Ibuprofen (advil) also undergoes chiral inversion In vitro tests show that R(-) ibuprofen is less potent than the S(+)-enantiomer in inhibiting prostaglandin synthesis When both enantiomers were given in combination or alone, an interesting thing happened…. R(-)-ibuprofen S(+)-ibuprofen Increased formation of ester glucuronide conjugates Slide21:  In summary…. Chiral carbons in a molecule may cause no differences in the potency of the enantiomers Enantiomers may have opposing effects Enantiomers can have beneficial/therapeutic effects and toxic effects One enantiomer may be more potent than the other Slide22:  How does chirality relate nasal decongestion? Slide24:  Easson & Stedman hypothesis (1933) Sequence of 3 key receptor elements and 3 substituents attached to asymmetric carbon center are complementary If complementary aligned isn’t present, leads to inactivity or lesser activity (Biochem J, 1933, 27:1257) Slide25:  Ephedrine Pseudoephedrine Slide26:  An example of stereoisomer activity on similar receptors was examined by Vansal and Feller (1999) (Biochem Pharmacol, 1999, 58: 807) Slide27:  Do repeated doses of EPH or PDE causes any effects at the receptor level? (Arch Int Pharmacodyn Ther, 1986, 174: 454) Tachyphylaxis has been associated with continuous EPH dosing When equipotent doses of EPH were used on an isolated heart assay, Slide28:  1S,2S-PDE 1S,2R-EPH Hypothesized that the differences in tachyphylaxis is due to 1S,2S-PDE and 1S,2R-EPH acting more like indirect sympathomimetic amines Slide29:  Does tachyphylaxis occur in an in vivo setting? Unlike isolated heart assay, opposite effects of isomers on tachyphylaxis occured When equipressor doses were used, 1R,2S-EPH was observed to be the least tachyphylactic and complete tachyphylaxis did not occur even after 14 doses Surprisingly, tachyphylaxis occurred with 1S,2S-PDE after 3 doses where vasopressor activity disappeared (J Pharmacol Exp Ther, 1965, 148:158) Slide30:  Receptors specific for EPH and PDE Both EPH and PDE are sympathomimetic agents Both act directly and indirectly adrenoceptors in the body Adrenoceptors are subdivided into two classes: α and β receptors of the CNS and PNS Generally, activation leads to opposite effects Belong to the sympathetic nervous system Distribution of receptors is tissue specific Endogenous sympathomimetic agents: Norepinephrine (NorE), epinephrine (Epi) Slide31:  Which is the better nasal decongestant… if they’re similar in structure? Use roth paper (Ann Otol, 1977, 86: 235) From a safety point of view, PDE is better do to its lower pressor potency and ability to increase HR (J Pharmcol Exp Ther, 1965, 148:158) Between EPH and PDE, PDE produces a greater degree of nasal decongestion without as much cardiovascular/toxic side-effects Both EPH and PDE have approximately equal potencies in bronchodiating abilities In terms of vasopressor activity, marked differences are seen in potencies and activity (J Pharmacol Exp Ther, 1965, 148:158) 1R,2S-EPH > 1S,2R-EPH > 1S,2S-PDE > 1R,2R-PDE Slide33:  How does PDE cause nasal decongestion? Effect is produced by constricting blood vessels in the vasculature of the nasal muscosa Occurs through direct-acting and indirect-acting mechanisms Slide34:  IP3 Direct-acting mechanisms of PDE 1.Binding of PDE to α1 adrenoceptors activates the DAG/IP3 signaling pathway PLC DAG Calcium Stores Slide35:  Direct-acting mechanisms of PDE (Cont’d) 2. Binding of PDE to α1 or α2 adrenoceptors may open membrane bound calcium channels Gq? Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Slide36:  Indirect-acting mechanism of PDE 1. Displacing norepinephrine in the vesicles terminal Synaptic Vesicle Vesicular monoamine transporter NorE carrier (Uptake 1) Slide37:  Indirect-acting mechanism of PDE (Cont’d) 2. Blocking reuptake of norepinephrine Synaptic Vesicle Vesicular monoamine transporter NorE carrier (Uptake 1) Slide38:  So which mechanism does PDE really use? (J Pharmacol Exp Ther, 2003, 307: 138) Ki values for PDE at human α1A receptors has been reported BUT value was considered almost negligible by researchers Compared to the other ephedrine isomers, it was found to have the highest inhibition activity at NorE uptake transporters Compared to (-)-EPH, it was weaker at causing release of NorE Recently, a study screened the EPH isomers against a receptorome and NorE uptake proteins Slide39:  Indirect-acting mechanism of PDE (Cont’d) 2. Blocking reuptake of norepinephrine Synaptic Vesicle Vesicular monoamine transporter NorE carrier (Uptake 1) Slide40:  Are single enantiomers the way to go? (Nat Rev Drug Dis, 2002, 1: 753) Up to late 1980s, racemic mixtures were still being released onto the market A “chiral switch” in drug design is occuring where older drugs coming off patents are being resubmitted as single enantiomers From a business stand-point, it’s a way for developers to hold on to patents From a health perspective, it means that older, “toxic” racemic drugs can be released in a “safe” form You can not assume that the “chiral switch” is a safe alternative... R(+)-thalidomide is the “non-teratogenic” form When it is in the body, it may actually switch to S(-)-enantiomer Slide41:  Recommended Readings Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA. (2003). In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates. J Pharmacol Exp Ther, 307: 138. Nagase H, Yajima Y, Fujii H, Kawamura K, Narita M, Kamei J, Suzuki T. (2001). The pharmacological profile of delta opioid receptor ligands, (+) and (-) TAN-67 on pain modulation. Life Sci, 68: 2227. Lee EJ, Williams K, Day R, Graham G, Champion D. (1985). Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol, 19: 669. Slide43:  Pseudoephedrine acts on alpha adrenoceptors causing vasoconstriction -vasoconstriction causes decrease in nasal airway resistance -it doesn’t actually clear out mucous. Receptors specific for pseudoephedrine Where they’re located -different subtypes -signal trans mech -how they all relate to each of the indicated uses Slide44:  Structural similarities of EPH and NorE Endogenous ligand for α or β adrenoceptors Synthetic ligand that non-specifically binds to α or β adrenoceptors (Electrophoresis, 1999, 20:2458) Slide45:  α-adrenoceptors Separated into 2 distinct classes: α1 and α2 Each class can be further subdivided into other classes (ie. α1-A) α1= located intrasynaptically on smooth muscle or postsynaptically in CNS α2= found in both CNS and PNS as well as on blood vessels Generally, α1 adrenoceptors= postjunctional in nervous system α2 adrenoceptors= prejunctional in nervous system α1 is normally coupled to the Gq g-protein signal transduction pathway α2 is normally coupled to either Gs or Gi leading to increases or decreases in cAMP Slide46:  β-adrenoceptors All β-adrenoceptors have the same second messenger system: Cyclic AMP Separated into four distinct subtypes: β1, β2, β3, β4 Distinguished by their affinities for Epi and NorE β1= primarily located on cardiac tissue β2= blood vessels, bronchi, GI tract (just to name a few) β3=Primarily in adipose tissue β4= Identified in cardiac tissue (not fully characterized) Slide47:  Structure of adrenoceptors Structural related to other GPCRs Have the characteristic 7 transmembrane-spanning helices The 3 β-adrenoceptors share roughly 60% sequence homology α1-adrenoceptors subtypes share 70% homology Similarly α2-adrenoceptor subytpes also have 70% homology Homology among the subclasses of α and β adrenoceptors is 30-40%

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