of
`
`related
`
`has supported this concept Compounds studied pos-
`for
`reversible
`features
`sess appropriate structural
`and highly selective association with an enzyme If
`in addition the compounds carry reactive groups
`forming covalent bonds the substrate
`capable of
`irreversibly bound
`to the drugreceptor
`may be
`complex by covalent bond formation with reactive
`to the active site In studies with
`groups adjacent
`reversibly binding antimetabolites that carried addi-
`groups of varying
`tional alkylating and acylating
`selective irreversible binding by the
`reactivities
`and glu-
`enzymes lactic
`dehydrogenase
`has been demonstrated The
`tamic dehydrogenase
`response has been attributed to the
`selectivity
`covalent bond between the carbo-
`formation of
`substituent
`of 5-carbophenoxy-
`phenoxyamino
`primary amino group in
`aminosalicylic acid and
`and
`between
`the
`glutamic dehydrogenase8
`maleamyl substituent of 4-maleamylsalicylic acid
`sulfhydryl group in lactic dehydrogenase.9
`and
`Assignments of covalent bond formation with spe-
`on the fact
`cific groups in the enzymes are based
`system of
`carbonyl
`that
`the
`a/3-unsaturated
`malearnyl groups reacts most rapidly with sulfhydryl
`groups much more slowly with amino groups and
`extremely slowly with hydroxyl groups In contrast
`react only with
`group will
`the carbophenoxy
`pri-
`protein The diuretic drug
`mary amino group on
`see Chap 13 is
`an
`a/3-un-
`acid
`ethacrynic
`to act by covalent bond
`saturated ketone
`thought
`formation with sulfhydryl groups of
`ion transport
`systems in the renal tubules
`
`OH
`
`COOH
`
`II
`
`C6H50
`
`5-CarbophenoxyamiflOSaliCyliC
`
`Acid
`
`CN
`
`II
`
`OH
`
`COOH
`
`COOH
`4-Maleamylsalicylic Acid
`
`Other examples of covalent bond formation be-
`site include the
`tween drug and biologic receptor
`reaction of arsenicals and mercurials with essential
`sulihydryl groups the acylation of bacterial cell wall
`by penicillin and the inhibition of
`constituents
`cholinesterase by the organic phosphates
`
`DRUG..RECEPTOR INTERACTIONS
`
`29
`
`It
`
`is desirable that most drug effects be reversible
`forces must be
`relatively weak
`For
`this to occur
`complex yet be strong
`involved in the drugreceptor
`enough that other binding sites will not competi
`tively deplete the site of action Compounds with
`high degree of structural specificity may orient sev
`eral weak-binding groups such that the summation
`of their interactions with specifically oriented corn-
`plementary groups on the receptor will provide
`stable combina
`total bond strength sufficient
`for
`tion
`Consequently for drugs acting by virtue of their
`structural specificity binding to the receptor site
`will be carried out by hydrogen bonds ionic bonds
`van der
`iondipole and dipoledipole interactions
`forces Ionization at physio
`Waals and hydrophobic
`logic pH would normally occur with the carboxyl
`sulfonamido and aliphatic amino groups as well as
`the quaternary ammonium group at any
`These
`ionic bonds are frequently found
`sources of potential
`be
`in active drugs Differences
`in electronegativity
`tween carbon and other atoms such as oxygen and
`nitrogen lead to an unsymmetric distribution of
`electrons dipoles that are also capable of forming
`weak
`bonds with regions of high or low electron
`ions or other dipoles Carbonyl
`density such as
`ester amide ether nitrile and related groups that
`contain such dipolar functions are frequently found
`locations in structurally specific drugs
`in equivalent
`Many examples may be found among the potent
`agents and local
`analgesics the cholinergic-blocking
`anesthetics
`The relative importance of the hydrogen bond in
`the formation of
`complex is difficult
`drugreceptor
`to assess Many drugs possess groups such as car-
`bonyl hydroxyl amino and imino with the struc
`tural capabilities of acting as acceptors or donors in
`the formation of hydrogen bonds However
`such
`groups would usually be solvated by water as would
`on
`receptor
`the corresponding
`groups
`biologic
`net change in free energy would be
`Relatively little
`bond with
`hydrogen
`expected
`in exchanging
`water molecule for one between drug and receptor
`However
`combination several
`drugreceptor
`in
`forces could be involved including the hydrogen
`bond which would contribute to the stability of the
`interaction Where multiple hydrogen bonds may be
`formed the total effect may be sizeable such as that
`demonstrated by the stability of the protein a-helix
`and by the stabilizing influence of hydrogen bonds
`between specific base pairs in the double helical
`structure of DNA
`van der Waals forces are attractive forces created
`by the polarizabiity of molecules and are exerted
`when any
`atoms
`two uncharged
`approach
`very
`closely Their strength is inversely proportional
`to
`
`

`
`30
`
`PHYSICOCHEMICAL
`
`PROPERTIES IN RELATION TO BIOLOGICAL ACTION
`
`and changed
`evolved
`ism has
`significantly in the
`years since its introduction by Langmuir2 in 1919
`Langmuir while seeking
`correlation that would
`explain similarities in physical properties for noniso
`meric molecules defined isosteres as compounds or
`groups of atoms having the same number and ar
`of electrons Those isosteres that were
`rangement
`isoelectric i.e with the same total charge as well
`as same number of electrons would possess similar
`physical properties For example the molecules N2
`and CO both possessing 14 total electrons and no
`show similar physical properties Related
`charge
`examples described by Langmuir were CO2 and N20
`and NCO
`and
`With increased understanding of the structures of
`less emphasis has been
`on the
`molecules
`placed
`number of electrons
`for variations in by-
`involved
`bridization during bond formation may lead to con-
`siderable differences in the angles the lengths and
`the polarities of bonds formed by atoms with the
`same number of peripheral electrons Even the same
`atom may vary widely in its structural and elec
`when it
`forms
`tronic characteristics
`part of
`functional group Thus nitrogen is part of
`different
`planar structure in the nitro group but forms the
`pyramidal structure in ammonia and the
`apex of
`amines
`Groups of atoms that
`impart similar physical or
`chemical properties to molecule because of simi
`larities in size electronegativity or stereochemistry
`are now frequently referred to under
`the general
`isostere The early recognition that benzene
`term of
`and thiophene were alike in many of their properties
`led to the term ring equivalents
`for the vinylene
`
`group CHCH and divalent sulfur S-
`
`correspondingly
`
`flat
`
`the seventh power of the distance Although individ-
`ually weak the summation of their forces provides
`in higher molecular weight
`significant bonding factor
`compounds For example it
`is not possible to distill
`normal alkanes with more than 80 carbon atoms
`because the energy of about 80 kcal/mol
`required to
`separate the moecu1es is approximately equal to the
`carboncarbon covalent
`energy required to break
`bond Flat structures
`such as aromatic rings per-
`mit close approach of atoms With vm der Waals
`for each
`force approximately 0.5 to 1.0 kcal/mol
`benzene ring would be
`atom about six carbons
`hydrogen bond
`necessary to match the strength of
`The aromatic ring is
`frequently found
`in active
`drugs and
`reasonable explanation for its require-
`ment
`for many types of biologic activity may be
`derived from the contributions of this flat surface to
`van der Waals binding to
`receptor area
`The hydrophobic
`bond is
`used to ex-
`concept
`plain attractive interactions between nonpolar
`re-
`the receptor and the drug Explanations
`gions of
`such as the isopropyl moiety of the drug fits into
`the
`cleft on the receptor composed of
`hydrophobic
`the amino acids valine
`side chains of
`hydrocarbon
`isoleucine and leucine are commonly used to ex-
`plain why
`substituent at
`nonpolar
`position on the drug molecule is important
`for activ-
`ity Over the years the concept of hydrophobic bonds
`has developed There has been considerable contro-
`versy over whether or not
`the bond actually exists
`Thermodynamic arguments on the gain in entropy
`decrease in ordered state when hydrophobic groups
`partial collapse of the ordered water struc-
`cause
`ture on the surface of
`the receptor have been pro-
`bonding model
`posed
`hydrophobic
`to validate
`There are two problems with this concept First the
`implies repulsion The term for
`term hydrophobic
`attraction is hydrophilicity Second and perhaps
`more importmt there is no truly water-free region
`in the areas
`on the receptor This is true even
`side amino acid
`populated
`by the nonpolar
`side
`chains An alternate approach is to consider only the
`concept of hydrophilicity and lipophilicity The pre-
`dominating water molecules solvate polar moieties
`squeezing the nonpolar
`residues toward
`effectively
`each other
`
`particular
`
`has led to replacement of
`This concept
`the sulfur
`atom in the phenothiazine ring system of tranquiliz
`ing agents with the vinylene group to produce the
`see
`class
`of antidepressant
`dibenzazepine
`drugs
`Chap 10 The vinylene group in an aromatic ring
`system may be replaced by other atoms isosteric to
`sulfur such as oxygen furan or NH pyrrole how-
`in such
`cases aromatic character
`ever
`is signifi
`cantly decreased
`isosteric pairs that possess similar
`Examples of
`steric and electronic configurations
`are the carboxyl
`ate COO and sulfonamido SO2NR ions ketone
`CO and sulfone SO2 groups chloride Cl and
`0- sulfide S-- amine NH- and
`trifluoromethyl CF3 groups Divalent
`
`Isosterism
`
`The term isosterism has been widely used to de-
`components
`scribe the selection of structural
`the
`steric electronic and solubility characteristics
`which make them interchangeable
`in drugs of
`same pharmacologic
`class The concept
`of
`isoster-
`
`the
`
`of
`
`methylene
`
`CH2
`groups although dissimilar
`are sufficiently alike in their steric
`electronically
`nature to be frequently interchangeable in drugs
`Compounds may be altered by isosteric replace
`ments of atoms or groups to develop analogues with
`select biologic effects
`or
`to act
`to
`as antagonists
`normal metabolites
`Each
`compounds
`series of
`
`ether
`
`

`
`specific biologic effect must be considered
`showing
`separately for there are no general
`rules that will
`predict whether biologic activity will be increased or
`decreased It appears that when isosteric
`replace-
`involves the bridge connecting groups neces-
`ment
`like effects
`gradation of
`given response
`sary for
`results with steric factors bond angles and relative
`polar character being important Some examples of
`this type are as follows
`
`-__ OH
`
`Se
`
`NH CH2
`
`Antibacterial
`
`HOXCH2
`
`NH2
`
`CH
`
`Thyroid Hormone Analogs
`
`CH2
`
`R--XCH2CH2N
`
`Antihistamines
`
`Cholinergic Blocking Agents
`
`NH CH2
`CONH cos
`
`coo
`
`When
`part of molecule in
`in
`group is present
`which it may be involved in an essential
`interaction
`or may influence the reactions of neighboring groups
`isosteric replacement sometimes produces analogues
`that act as antagonists Some examples from the
`field of cancer chemotherapy are
`
`rCH
`
`Adenine
`
`Hypoxanthine
`
`6-Mercaptopurine
`
`NH2
`OH
`
`SH
`
`Metabolites
`
`Antimetabolile
`
`DRUG-RECEPTOR INTERACTIONS
`
`31
`
`similar fashion replacement of the hydroxyl
`In
`folic acid by the
`group of pteroylglutamic acid
`amino group leads to methotrexate an antagonist
`in the treatment of certain types of cancer
`useful
`As
`develops of the nature
`better understanding
`the interactions between drug metabolizing en-
`of
`zymes and biologic receptor selection of
`isosteric
`groups with particular electronic solubility and
`steric properties should permit the rational prepara
`tion of more selectively acting drugs But
`in the
`meanwhile results obtained by the systematic appli
`cation of the principles of isosteric replacement are
`aiding in the understanding
`the nature of
`these
`of
`receptors
`
`Steric Features of Drugs
`
`possess
`
`Regardless of the ultimate mechanism by which the
`the drug must ap
`drug and the receptor
`interact
`proach the receptor
`and fit
`closely to its surface
`Steric factors determined by the stereochemistry of
`and that of
`the drug
`site surface
`the receptor
`molecules are therefore of primary importance
`in
`determining the nature and the efficiency
`the
`of
`interaction With the possible excep
`drugreceptor
`drugs must
`the general anesthetics
`such
`tion of
`high degree of structural
`to
`specificity
`receptor
`response at
`initiate
`Some structural
`features contribute
`high degree
`rigidity to the molecule For example
`of structural
`aromatic
`rings are planar and the atoms attached
`directly to these rings are held in the plane of the
`aromatic ring Hence the quaternary nitrogen and
`carbamate oxygen attached directly to the benzene
`ring in the cholinesterase inhibitor neostigmine are
`restricted to the plane of the ring and consequently
`these atoms is
`of at
`least
`the spatial arrangement
`established
`
`particular
`
`CH3
`CH
`CH3
`
`CH3
`
`CH3
`
`cO
`
`Neostigmine
`
`The 6-NH2 and 6-OH groups appear to play es
`sential roles in the hydrogen-bonding
`interactions of
`base pairs during nucleic acid replication in cells
`The substitution of the significantly weaker hydro-
`gen-bonding isosteric sulfhydryl groups results in
`partial blockage of this interaction and
`decrease in
`the rate of cellular synthesis
`
`The relative positions of atoms attached direct-
`ly to multiple bonds are also fixed For the double
`bond cis and
`trans isomers result For example
`diethyistilbestrol exists in two fixed stereoisomeric
`forms trans-Diethylstilbestrol
`is estrogenic whereas
`
`

`
`32
`
`PHYSICOCHEMICAL
`
`PROPERTIES IN RELATION TO BIOLOGICAL ACTION
`
`the cis-isomer is oniy 7% as active In trans-diethyl-
`resonance interactions and minimal steric
`stilbestrol
`interference tend to hold the two aromatic rings and
`connecting ethylene carbon atoms in the same plane
`
`Equatorial
`
`and axial
`
`sub-
`
`stitution in the chair
`
`lorm of cyclo
`
`hexane
`
`25
`
`/\
`
`OH
`
`HO
`
`HO
`
`trans-Diethylstilbestrol
`
`HO
`
`CC2H5
`
`C\
`
`C2H5
`
`cis-DtethylstHbestrol
`
`biologic receptor
`
`structurally spe-
`
`Geometric isomers such as the cis and the trans
`isomers hold structural
`features at different relative
`positions in space These isomers also have sigriifi-
`cantly different physical and chemical properties
`Therefore their distributions in the biologic medium
`for inter-
`as well as their capabilities
`are different
`acting with
`in
`cific manner
`More subtle differences exist
`for conformational
`isomers Similarly to geometric isomers these exist
`in space for the atoms or
`as different arrangements
`single classic structure Rotation about
`groups in
`bonds allows interconversion
`of conformational
`iso-
`mers however
`an energy barrier between isomers is
`often sufficiently high for their
`independent
`exis-
`tence arid reaction Differences in reactivity of func-
`tional groups or interaction with biologic receptors
`may be due to differences in steric requirements In
`certain semirigid ring systems such as the steroids
`isomers show significant differences
`conformational
`see Chap 18 Methods
`for
`in biologic activities
`these energy barriers will be discussed
`
`calculating
`
`later
`The principles of conformational analysis have
`the more
`some generalizations
`about
`established
`stable structures for reduced nonaromatic ring sys-
`tems In the cyclohexane derivatives bulky groups
`tend to be held approximately in the plane of the
`ring the equatorial position Substituents attached
`the
`to bonds perpendicular
`to the general plane of
`ring axial position are particularly susceptible to
`steric crowding Thus 13-diaxial substituents larger
`than hydrogen may repel each other
`twisting the
`flexible ring and placing the substituents
`in the less
`crowded equatorial conformation
`
`reduced
`
`Similar calculations may be made for
`such
`ring systems
`substituted
`heterocyclic
`as
`piperidines Generally an equilibrium mixture of
`conformers may exist For example the potent anal-
`gesic trimeperidine see Chap 17 has been calcu
`largely in the form in which the bulky
`lated to exist
`phenyl group is in the equatorial position this form
`being favored by
`kcal/mol over the axial species
`The ability of molecule to produce potent analgesia
`has been related to the relative spatial positioning of
`flat aromatic nucleus
`connecting
`aliphatic or
`alicyclic chain and
`nitrogen atom which exists
`H.2 It
`largely in the ionized form at physiologic
`that one of the conformers would
`might be expected
`be responsible for the analgesic activity however
`here it appears that both the axially and the equato
`group may contribute
`phenyl
`oriented
`In
`related isomers the conformations of
`structurally
`which are fixed by the fusion of an additional ring
`both compounds in which the phenyl group is the
`axial and those in which it
`is in the equatorial
`position have equal analgesic potency.22
`related study of conformationally rigid di-
`In
`astereoisomeric analogues of meperidine the endo
`than was the exo
`phenyl epimer was more potent
`isomer.23 However
`endo-isomer
`the
`penetrated
`brain tissue more effectively because of slight dif
`in PKa values and partition
`ferences
`coefficients
`between the isomers This emphasizes the impor
`tance of considering differences in physical proper-
`ties of closely related compounds before interpreting
`on
`differences
`activities
`steric
`in biologic
`solely
`func
`grounds and relative
`tional groups
`Open chains of atoms which form an important
`part of many drug molecules are not equally free to
`assume all possible conformations there being some
`that are sterically preferred.24 Energy barriers to
`the chains are present owing to
`free rotation of
`interactions of nonbonded atoms For example the
`atoms tend to position themselves in space such that
`they occupy staggered positions with no two atoms
`directly facing eclipsed Thus for butane at 370
`the calculated relative probabilities for four possible
`show that
`conformations
`the maximally extended
`trans form is favored
`the two equivalent
`over
`bent skew forms The cis form in which all of the
`atoms are facing or eclipsed is much hindered and
`
`rially
`
`spatial positioning of
`
`

`
`CH3
`
`COH
`
`CH2
`
`CH3
`
`Trimeperidine equator/a/-phenyl
`
`H3
`CH2 OH3
`
`Trimeperidine axia/-phenyl
`
`CH3
`
`CH
`
`CH2
`
`CH2
`
`CH2
`
`Equatorial-phenyl analgesic
`ED50 18.4 mg/kg
`
`CH
`
`Ax/a/-phenyt
`analgesic
`ED50 18.7 mg/kg
`
`Ring-fused Analgesics
`
`DRUG-RECEPTOR
`
`INTERACTIONS
`
`33
`
`trans 1.0
`
`skew 0272
`
`skew 0.272
`
`c/s 0.001
`
`Relative probabilities for the existence of conformations
`
`of butane
`
`in
`
`their
`
`amines It should be noted that
`such amines are
`largely protonated at physiologic pH arid exist
`form Accordingly
`charged
`tetra-covalent
`stereochemistry closely resembles
`that of carbon
`in the following diagrams the hydrogen
`although
`atoms attached to nitrogen are not shown As may
`be expected the fully extended trans form with
`ring and the nitro
`maximal separation of the phenyl
`smaller population of the
`gen atom is favored and
`skew forms in which the ring and
`two equivalent
`the nitrogen are closer
`together exists in solution
`Introduction of an a-methyl group alters the fa
`vored posItion of the trans form as positioning of
`the bulky methyl group away from the phenyl group
`skew form
`in non
`decrease
`also results in
`bonded interactions Clearly skew form with both
`the methyl and the amine group close to phenyl
`is
`less favorable The overall
`result
`reduction in
`is
`distance between the aromatic
`the average
`group
`and the basic nitrogen atom in a-methyl-substituted
`influences the
`/3-arylethylamines This steric factor
`strength of the binding interaction with
`biologic
`required to produce
`given pharmacologic
`
`receptor
`
`is possible that the altered stereochemistry
`effect
`It
`of a-methyl-/3-arylethylamines may partially ac
`for their slow rate of metabolic deamination
`count
`see Chap 11
`
`to be
`
`1000 molecules may be expected
`only about
`in this conformation at normal temperatures
`Nonbonded interactions in polymethylene chains
`the most extended trans conforma-
`tend to favor
`tions although some of the partially extended skew
`conformations
`branched methyl group
`also exist
`reduces somewhat
`the preference for the trans form
`the chain and therefore the
`in that portion of
`probability distribution for the length of the chain is
`shifted toward the shorter distances This situation
`the
`in substituted chains that contain
`is present
`elements of many drugs such as the /3-phenylethyl-
`
`trans
`
`skew
`
`skew
`
`Conformantions of -phenylethylamines
`
`

`
`34
`
`PHYSICOCHEMICAL
`
`PROPERTIES IN RELATION To BIOLOGICAL ACTION
`
`trans
`
`Stabilizing planar structure of esfers
`
`trans-planar
`
`form
`
`resonance
`
`form
`
`RO
`
`cr5-planar
`
`form
`
`skew form
`
`skew form
`
`Conformations of a-Mefhyl--phenylefhylamines
`
`trans-planar
`
`form
`
`resonance
`
`form
`
`c/s-planar
`
`form
`
`Sf abilizing planar strucfure of amides
`
`the central bonds of
`
`is favored
`
`The introduction of atoms other
`than carbon into
`chain strongly influences the conformation of the
`chain Because of resonance contributions of forms
`in which
`double bond occupies
`esters and amides
`planar configuration
`in which minimal steric interference
`of bulky sub-
`stituents occurs Hence an ester
`is mainly in the
`trans rather than the cis form For the same rea-
`son the amide linkage is essentially planar with the
`more bulky substituents occupying the trans posi-
`chain
`tion Therefore ester and amide linkages in
`tend to hold bulky groups in
`plane and to separate
`them as far as possible As components of the side
`chains of drugs ester and amide groups favor
`fully
`extended chains and also add polar character
`that segment of the chain
`The foregoing considerations make it clear
`that
`the ester linkages in succinyl choline provide both
`polar segment which is readily hydrolyzed by plasma
`cholinesterase see Chap 12 and additional stabi-
`lization to the fully extended form This form is also
`favored by repulsion of
`the positive charges at
`the
`ends of the chain
`The
`stereochemical
`favored
`conformations
`by
`considerations may be further influenced
`by in-
`between specific groups in
`tramolecular
`interactions
`involving attrac-
`forces
`
`to
`
`the molecule Electrostatic
`
`tions by groups of opposite charge or repulsion by
`groups of like charge may alter molecular size and
`shape Consequently the terminal positive charges
`on
`the polymethylene bis-quaternary
`ganglionic
`blocking agent hexamethonium and the neuromus
`agent decamethonium make it most
`cular-blocking
`these molecules are maxi
`the ends of
`likely that
`mally separated in solution
`
`CH33NCH2NCH33
`Hexamethonium
`
`Decamethonium
`
`10
`
`In some cases dipoledipole interactions appear
`to influence structure in solution Methadone may
`cyclic form in solution because of
`exist partially in
`clipolar attractive forces between the basic nitrogen
`and carbonyl
`In such
`conformation it
`group.25
`the conformationally more rigid
`closely resembles
`potent analgesics morphine meperidine and their
`analogues see Chap 17 and it may be this form
`that interacts with the analgesic receptor
`An intramolecular hydrogen bond usually formed
`between donor OH and NH groups and ac
`
`ceptor oxygen
`
`and nitrogen
`
`atoms
`
`OH3
`
`OH3
`
`\H
`
`OH3
`
`II
`
`Extended form of succinyl choline
`
`OH3
`
`OH3
`
`OH
`
`

`
`CH3
`
`CH3
`
`CH3
`
`cH3
`
`Ring conformabon of methadone
`interactions
`
`by dipolar
`
`to add stability to
`might be expected
`particular
`drug in solution However
`in
`conformation
`of
`aqueous solution donor and acceptor groups tend to
`to water and little
`gain in free energy
`be bonded
`by the formation of an
`be achieved
`would
`in-
`tramolecular hydrogen bond particularly if unfavor-
`able steric factors involving nonbonded interactions
`were introduced in the process Therefore it
`is likely
`secondary
`internal hydrogen bonds play only
`that
`role to steric factors in determining the conforma-
`tional distribution of flexible drug molecules
`
`Con formational Flexibility and Multiple Modes
`of Action
`
`it
`
`the conformational
`It has been proposed that
`flexi-
`bility of most open-chain neurohormones such
`as
`epinephrine serotonin and related
`acetylcholine
`such
`as his-
`biomolecules
`active
`physiologically
`to be pro
`tamirie permits multiple biologic effects
`the ability to
`duced by each molecule by virtue of
`different and unique conformation with
`in
`interact
`different biologic receptors Thus it has been sug-
`gested that acetyicholine may interact with the mus-
`parasympathetic
`carinic receptor of postganglionic
`nerves and with acetyicholinesterase
`in the fully
`and in
`extended conformation
`different more-
`folded structure with the nicotinic receptors at gan-
`glia and at neuromuscular
`junctions.2627 Acetyl-
`quasi-ring form in the
`choline bromide exists in
`crystal with an N-methyl hydrogen atom close to
`hydrogen bond with the
`and perhaps forming
`In solution however
`backbone
`is able
`oxygen.28
`series of conformations
`continuous
`to assume
`favored
`some of which
`others.27
`
`are energetically
`
`over
`
`mol-
`
`Conformationally
`rigid acetyicholinelike
`have been used to study the relationships
`ecules
`between these various possible conformations
`of
`acetylcholine and their biologic effects
`-trans-2-
`trimethylammonium iodide in
`Acetoxycyclopropyl
`which the quaternary nitrogen atom and acetoxyl
`conformation approximat-
`in
`groups are held apart
`the extended conformation of acetyl-
`ing that of
`five times more active
`than
`choline was about
`
`DRUG-RECEPTOR
`
`INTERACTIONS
`
`35
`
`as
`
`acetylcholine
`
`in its muscarinic effect on dog blood
`pressure and equiactive to acetylcholine in its mus
`on the guinea pig ileum.2 The
`carinic effect
`trans-isomer was hydrolyzed by acetylcholinesterase
`to the rate of hydrolysis of acetyl
`rate equal
`at
`choline It was inactive
`nicotinic agonist
`In
`as
`-trans-isomer and
`the mixed
`the
`contrast
`-cis-isomers were 1/500
`and 1/10000
`in muscarinic
`on
`tests
`active
`as
`acetylcholine
`guinea-pig ileum and were inactive as nicotinic ago
`relationship be-
`nists Similarly the trans-diaxial
`tween the quaternary nitrogen and acetoxyl group
`led to maximal muscarinic response and rate of
`in
`series
`hydrolysis by true acetylcholinesterase
`isomeric 3-trimethylammonium-2-acetoxylde-
`of
`These
`results could be interpreted that
`calms.30
`trans conforma
`either acetylcholine was acting in
`tion at the muscarinic receptor and was not acting
`cisoid conformation at the nicotinic receptor or
`in
`the nicotinic response is highly sensitive
`to
`that
`steric effects of substituents being used to orient the
`molecule
`
`cH3
`
`/CH
`
`-O cc
`
`Quasi-ring form of acetyicholine
`
`cH3 /C3
`CH3
`
`\\co
`
`cti3
`
`Extended conformation of acetyicholine
`
`in
`
`re
`In contrast with the concept of acetylcholine
`and nicotinic receptors
`acting with muscarinic
`in
`different conformations Chothia3t has proposed that
`in the same conformation
`interacts
`acetyicholine
`different manner with each receptor The
`but
`of acetyicholine Fig 2-8 are primar
`conformations
`Cg and
`ily defined by rotations about
`the
`01 bonds because
`Se
`the C1
`quence and the 02C401Cg ester group exist
`owing to steric and
`largely in planar conformations
`and several selec
`resonance factors Acetylcholine
`and
`have
`been
`agents
`tive muscarinic
`nicotinic
`shown to be in closely similar conformations in the
`
`

`
`36
`
`PHYSICOCHEMICAL
`
`PROPERTIES IN RELATION TO BIOLOGICAL ACTION
`
`II
`
`TcH3
`
`trans-diaxial 3TrimethyIammonium-2-acetoxydecaIin
`
`FIG 2-8
`
`Acetylcho/ine
`
`conformation and receptor specificity
`
`LCH3 CH3
`
`CCH3
`
`trans2-AcetoxycyclopropyI
`
`Trimethylammonium
`
`Iodide
`
`CH3 CH3
`
`/\
`CH3
`
`II0C
`
`CH
`
`cim2-Acetoxycyclopropyl
`
`Trimethylammonium
`
`Iodide
`
`In these compounds
`state.32
`the Ca
`CB
`crystal
`bond or its equivalent
`and
`is rotated so that the
`01 ether oxygen are about 600 to 75 from the cis
`The Ca CB
`1C4
`conformation
`coplanar
`atoms are essentially in
`trans planar extended
`chain This conformation presents
`methyl side
`plane close to C2 01 and C5 methyl
`defined by
`carbon and
`carbonyl side defined by
`plane close
`to C3 Cd and 02 carbonyl oxygen Compounds
`with high muscarinic and low nicotinic activity such
`trimethylammonium
`as
`trans-2-acetoxycyclopropyl
`iodide L-
`-acetyl-f3-methylcholine and muscarine
`show structures in the crystal state that have free
`access to their methyl sides whereas their carbonyl
`sides are blocked by the spatial position occupied by
`the extra methyl or methylene groups In preferen-
`tial nicotinic agonists such as L-
`-acetyl-a-meth-
`ylcholine the carbonyl side is exposed and access to
`the methyl side is blocked Chothia3 has proposed
`the methyl sides of acetylcholine and its pre-
`that
`dominantly muscarinic analogues interact with the
`muscarine
`receptor whereas it
`is the interaction
`with groups on the carbonyl
`side of acetylcholine
`and its nicotinic analogues that activates the nico-
`tinic receptor
`
`energy33
`form
`
`of
`
`With use of an approach that
`on
`focuses
`the
`than on conformationally
`parent molecule rather
`fixed analogues molecular orbital calculations
`have
`indicated that histamine may exist
`in two extended
`conformations
`of nearly equal and minimal
`than the earlier predicted
`rather
`coiled
`involving intramolecular hydrogen bonds.34
`In one extended conformation
`one imidazole
`ring nitrogen atom is about 4.55
`from the side
`chain nitrogen whereas in conformation
`this dis
`is about
`Histamine receptors
`have
`tance
`3.60
`been differentiated into at
`two classes there
`least
`requirements for stimula
`being different structural
`tion of smooth muscle such as the guinea pig ileum
`histamine H1-receptor blocked
`by classic antihis
`tamines and for
`the stimulation of secretion of
`gastric acid histamine H2-receptor not blocked
`by
`classic antihistamines It
`is proposed on the basis
`the internitrogen distance of closest approach of
`the relatively rigid antihistamine
`4.8
`0.2
`for
`triprolidine that histamine acts on smooth muscle
`in conformation
`H1-receptor
`in which the intra
`nitrogen distance of 4.55
`closely approximates the
`spacing found in the specific antagonist
`is further
`It
`presumed that the histamine-induced release of gas-
`tric acid may be brought about by
`histamine H2-
`interaction in an alternate conformation
`receptor
`such
`as confor
`of closer
`spacing
`mation
`The
`histamine H2-receptor
`antagonist35
`16 contains
`see Chap
`metidine
`uncharged
`polar residues on the side chain such as the thio
`
`internitrogen
`
`ci-
`
`HN/C
`
`HHH
`
`cc
`HN
`
`CH2
`CH
`H2
`
`HI\
`
`H\
`
`3.60
`
`Conformations
`
`of Histamine
`
`

`
`CH3O
`
`CcG
`
`4.8O
`
`Tnprolidine antihistamine
`
`NH
`
`NH
`CS
`or N-cyanoguanidine
`urea
`NCNNH
`NH
`These polar
`groups
`residues are separated from the imidazole ring by
`than the
`chains four-atoms long two-atoms
`longer
`dimethylene side chain of histamine It appears likely
`2-antagonist activity results from the interac-
`that
`tion of the side chain arid its polar residues with
`from that with which the
`region distinct
`receptor
`positively charged side chain of histamine interacts
`
`CH3
`
`HNN
`
`CN
`
`CH2SCH2CH2NHCNHCH3
`
`Cimetidine
`
`Optical
`
`Isomerism and Biologic Activity
`
`The widespread occurrence of differences in biologic
`isomers has been of particular
`actities for optical
`theories on the
`in the development
`of
`importance
`nature of drugreceptor
`interactions
`Diastereo-
`isomers compounds with two or more asymmetric
`same functional
`and
`have
`centers
`the
`groups
`therefore can undergo the same types of chemical
`the diastereoisomers e.g
`reactions However
`ephedrine pseudo ephedrine see Chap 11 have
`different physical properties undergo different rates
`of reactions have substituent groups that occupy
`different relative positions in space and the differ-
`ent biologic properties shown by such isomers may
`be accounted
`for by the influence of any of
`these
`factors on drug distribution metabolism or interac
`tion with the drug receptor
`However
`optical enantiomers also called optical
`antipodes mirror images present
`very different
`situation for they are compounds the physical and
`chemical properties of which are usually considered
`for their ability to rotate the plane
`identical except
`the com
`of polarized light Here one might expect
`pounds to have the same biologic activity However
`such
`is not
`of many of
`the enan-
`representative
`tiomers that have been investigated
`
`DRUG-RECEPTOR INTERACTIONS
`
`37
`
`As examples of compounds the optical
`isomers of
`which show different activities the following may be
`-hyoscyamine is 15 to 20 times more active
`cited
`as mydriatic than -hyoscyamine -hyoscine
`is 16 to 18 times as active as -f
`-epi
`-hyoscine
`nephrine is 12 to 15 times more active as
`vaso
`-epinephrine -norhomo
`than
`constrictor
`is 160 times more active
`epinephrine
`as
`pressor
`than
`-synephrine has
`-norhomoepinephrine
`60
`times the pressor activity of
`-synephrine
`-amino acids
`tasteless
`are either
`or bitter
`whereas -i- -amino acids
`-ascorbic
`are sweet
`has
`properties whereas
`good
`acid
`antiscorbutic
`-ascorbic acid has none
`that optical an
`Although it
`is well established
`tipodes have different physiologic activities there
`interpretations of why this is so Dif
`are different
`ferences in distribution of isomers without consider-
`ing differences in action at
`the receptor site could
`account
`isomers
`for different activities
`for optical
`formation with optically
`Diastereoisomer
`active
`components of the body fluids e.g plasma proteins
`could lead to differences in absorption distribution
`and metabolism Distribution could also be affected
`by preferential metabolism of one of
`the optical
`stereospecific enzyme e.g D-amino
`antipodes by
`acid oxidase