フェニルトロパンのリスト

フェニルトロパン( PT ) は、もともとコカインの構造修飾から派生した化合物のグループです。コカインとフェニルトロパンを区別する主な特徴は、ベンゼンで終わる 3 位にエステル官能基がないことです。そのため、フェニルは、コカインベンゾイルオキシが提供する追加のスペーサーなしでトロパン骨格に直接結合します(そのため、「フェニル」トロパンと呼ばれます) 。その本来の目的は、刺激機能を保持しながら、コカインの局所麻酔の「麻痺」能力に固有の心毒性を排除することでした (メチル化安息香酸エステルは、局所麻酔を引き起こすナトリウムチャネルをコカインがブロックするのに不可欠であるため) 。^[a]これらの化合物は、特に依存症治療において、治療への応用に関するさまざまな研究の道を示しています。用途は、その構造と構造活性相関によって異なり、コカイン依存症の治療から人間の脳内のドーパミン報酬系の解明、アルツハイマー病やパーキンソン病の治療まで多岐にわたります。（2008年以降、この物質プロファイルのカテゴリに分類される化学物質の種類のリストと列挙には継続的に追加が行われています。^[2]）特定のフェニルトロパンは、禁煙補助剤としても使用できます（ RTI-29を参照）。化合物の多くは、リサーチ トライアングル研究所の出版物で初めて解明されたため、「RTI」シリアル番号で命名されています (この場合、長い形式は「コカイン」の「類似体」を表す RTI-COC- n、またはこの記事で後述の番号のうち具体的には RTI-4229- nです) ^[b]同様に、他の多くの化合物は、スターリング ウィンスロップ製薬(「WIN」シリアル番号) とウェイク フォレスト大学(「WF」シリアル番号) にちなんで命名されています。以下は、製造され研究されているフェニルトロパン クラスの薬物の多くです。

コカインと同様に、フェニルトロパンは、ドーパミントランスポーターの「外向きに開いた」構造を安定化させるという点で、「典型的な」または「古典的な」（つまり「コカインのような」）DAT再取り込みポンプリガンドであると考えられています。フェニルトロパンとの極端な類似性にもかかわらず、ベンズトロピンやその他のものは、その点で「コカインのような」とは考えられておらず、より内向き（外向きに閉じた）構造状態と見なされるものを安定化させるという点で非定型阻害剤であると考えられています。^[5]

PT とコカインの違いについて考えると、コカインとフェニルトロパンのベンゾイルオキシとフェニル結合の長さの違いにより、後者の PT では芳香族ベンゼンの重心とトロパンの橋渡し窒素の間の距離が短くなります。この距離は、フェニルトロパンの場合は 5.6 Å 、コカインまたはベンゾイルオキシがそのままの類似体の場合は7.7 Åです。 ^[c]このフェニルトロパンが MAT の結合ポケットに収まる仕組みは、PT がコカインよりも行動刺激プロファイルが強いことを説明する 1 つの可能性として想定されています。^[d]

省略されたデータ用の表内の空白スペースには、「データなし」、「?」、「-」、または「—」を同じ意味で使用します。

• ^ɑ ·HCl（塩）として
• ^b ·HCl·2 H ₂ O （塩）
• ^cシンは、NETについては1,329、5-HTについては320という逆の値を示しています。

• ^ɑカニクイザル尾状核被殻におけるIC _{50 の}測定
• ^bとして ·HCl (塩)
• ^c as ·HCl·2 H ₂ O （塩）
• ^d NE _N

^ɑN =2 です

^ɑN =2 です

• ^{ɑ [ 3} H]DA取り込みの変位に対するKi値。
• ^{b [ 3H} ]5-HTの取り込みの置換に対するKi値
• ^{c [ 3H} ]NE取り込みの置換に対するKi値。
• ^d [ ³ H]5-HT取り込みと[ ³ H]DA取り込みの比。
• ^e [ ³ H]NE取り込みと[ ³ H]DA取り込みの比。

シクロプロピルエステルを使用すると、イソプロピルエステルを選択した場合よりもMAT保持が向上するようです。

^cyc Buを使用すると、^cyc PrホモログよりもDAT選択性が高くなりました。

N-デスメチルパロキセチンの同族体を参照

米国特許 5,736,123

✲RTI-183 と RTI-218 は、メチルとメトキシの間の「CON(OMe)Me」と「CON(Me)OMe」の違いが同じであることから、コピーエラーの可能性を示唆しています。

フランク・アイビー・キャロルの特許によれば、フェニルトロパンの二量体は、C2位がカルボキサミド構造構成（通常の固有のエクゴニンカルボメトキシとは対照的かつ離れている）へと変化して二重形態で結合しており、このような化合物は、生体内で活性に遅延されたプロドラッグであるため、特許が取得された可能性がある。^[3]

これらの複素環は、それらが由来するより単純なエステルの「生物学的等価物」と呼ばれることもあります。ββエステルを未反応のままにしておくことの潜在的な欠点は、加水分解可能であることに加えて、エネルギー的に有利なトランス配置にエピマー化される可能性があることです^[17]。これはコカインにも起こり得ます。

いくつかのオキサジアゾールには同じ数と種類のヘテロ原子が含まれていますが、それぞれの結合力は 8 ～ 15 倍の差があります。これは、水素結合に由来する親和性では説明できない結果です。

静電相互作用の可能性を探るため、モデル化合物34 (フェニルトロパン部分をメチル基に置き換えた) で分子静電ポテンシャル (MEP) を使用しました。原子の位置 A ～ C の近傍に注目し、原子位置 A 付近の静電ポテンシャルの最小値(Δ V _min (A)) を半経験的 ( AM1 ) 量子力学計算 (立体的および配座的矛盾が最小になるように複素環式環とフェニル環を重ね合わせた) で計算したところ、DAT での親和性と Δ V _min (A) の間に相関関係があることがわかりました。後者の値は、32c = 0、32g = -4、32h = -50、32i = -63 kcal/mol でした。

この傾向とは対照的に、Δ V _{min が}負に大きくなることは、上記とは逆の傾向である水素結合の強度の増加と相関関係にあることが分かっています。これは、2β置換基（少なくとも複素環式クラスの場合）は、コカイン様結合リガンドのこの置換基の推定水素結合モデルの代わりに、結合の静電的因子によって支配されていることを示しています。^[g]

注:ただし、テトラゾール環を作成するための代替方法がいくつかあります。サルタンの薬物合成スキームを参照してください。Bu ₃ SnN _{3 は}、アジ化水素(イルベサルタンを参照) よりも穏やかな試薬の選択肢です。

注意: p-フルオロフェニルは他のものよりも弱いです。RTI-145 は過酸化物ではなく、炭酸 メチルです。

^a WIN 35428の置換に対するKi値_。b
^IC ₅₀値。

不可逆的（フェニルイソチオシアネート）結合リガンド（Murthy, V.; Martin, TJ; Kim, S.; Davies, HML; Childers, SR（2008）。「ラット脳のモノアミントランスポーターにおける新規フェニルイソチオシアネートトロパン類似体の生体内特性評価」。Journal  of Pharmacology and Experimental Therapeutics。326（2）：587–595。doi ：10.1124/jpet.108.138842。PMID 18492949。S2CID 5996473  。) ^[23] RTI-76 : ^[24] 4′-イソチオシアナトフェニル (1R,2S,3S,5S)-3-(4-クロロフェニル)-8-メチル-8-アザビシクロ[3.2.1]オクタン-2-カルボキシレート。別名：3β-(p-クロロフェニル)トロパン-2β-カルボン酸p-イソチオシアナトフェニルメチルエステル。

HD-205（マーシーら、2007）^[25]

フェニルイソチオシアネートの共有結合部位の位置を、非フェニルトロパンコカイン類似体であるp-イソコックのものと比較した際の違いに注目してください。

One patent claims a series of compounds with biotin-related sidechains are pesticides.^[18]

WO 2004113297, Peters, Dan; Olsen, Gunnar M. & Nielsen, Elsebet Oestergaard et al., "Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", published 2004-12-29, assigned to NeuroSearch AS 

U.S. patent 2,001,047,028

CA 2112084 

U.S. patent 2,001,047,028

WO 2004072075, Peters, Dan; Nielsen, Elsebet Oestergaard & Olsen, Gunnar M. et al., "Novel 8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", published 2004-08-26, assigned to NeuroSearch AS 

Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η⁶-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule.^[1] (cf. the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. Bloom and Wheeler.^[29]).

21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity K_i values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.

The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)₃ whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.^[1]

• ^ɑThe binding data fit a two-site model better than a one-site model
• ^bThe K_i value for the one-site model was 124 ± 10 nM
• ^cIUPAC: [η⁶-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium
• ^dIUPAC: [η⁵-(pentamethylcyclopentadienyl)]-[η⁶-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate

• ^ɑIC₅₀ value for displacement of [H³]mazindol. IC₅₀ for cocaine 288 nM for displacement of [H³]mazindol

NS2359 (GSK-372,475)

It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.^[33] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.^[34]

^ɑThe N-demethylated variant of (i.e. compound code-name after dash)

"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).^[35]

^ɑThese values determined in Cynomolgus monkey caudate-putamen ^bThe radioligand used for 5-HTT was [³H]citalopram

See the N-methyl paroxetine homologues cf. di-aryl phenyltropanes for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class.

The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.

Bi- and tri-cyclic aza compounds and their uses.^[38][39]

• ^ɑIC₅₀ for displacement of [³H]cocaine. IC₅₀ for cocaine = 67.8 ± 8.7 (nM)
• ^bIC₅₀ values for displacement of [³H]WIN 35428
• ^cIC₅₀ values for displacement of [³H]citalopram
• ^dThe standard K_i value for the displacement of [³H]GBR 12935, [³H]paroxetine, and [³H]nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments

See: Bridged cocaine derivatives & N8 Tricyclic (2β—crossed-over) N8—to—3β replaced aryl linked (expansive front-bridged) cocaine analogues

U.S. patent 6,150,376

• ^ɑValue for displacement of [³H]WIN 35,428 binding @ DAT
• ^bValue for displacement of [³H]paroxetine binding to SERT
• ^cValue for displacement of [³H]nisoxetine from NET

Fused tropane-derivatives as neurotransmitter reuptake inhibitors. Singh notes that all bridged derivatives tested displayed 2.5—104 fold higher DAT affinity than cocaine. The ones 2.8—190 fold more potent at DAT also had increased potency at the other two MAT sites (NET & SERT); NET having 1.6—78× increased activity. (+)-128 additionally exhibited 100× greater potency @ SERT, whereas 132a & 133a had 4—5.2× weaker 5-HTT (i.e. SERT) activity. Front-bridged (e.g. 128 & 129) had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged (e.g. 130—133) preferred placement with DAT interaction.^[1] U.S. patent 5,998,405

1. 1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes.
2. 2° amine is reacted with Br(CH₂)nCO₂Et.
3. Base used to abstract proton α- to CO₂Et group and complete the tricyclic ring closure step (Dieckmann cyclization).

To make a different type of analog (see Kozikowski patent above)

1. Remove N-Me
2. Add ɣ-bromo-chloropropane
3. Allow for cyclization with K₂CO₃ base and KI cat.

(1R,2S,10R,12S)-15-methyl-15-azatetracyclo(10.2.1.0²,¹⁰.0⁴,⁹)pentadeca-4(9),5,7-trien-3-one^[3]

Parent compound of a series of spirocyclic cocaine benzoyl linkage modification analogs created by Suzuki coupling method of ortho-substituted arylboronic acids and an enol-triflate derived from cocaine; which technically has the three methylene length of cocaine analogues as well as the single length which defines the phenyltropane series. Note that the carbomethoxyl group is (due to constraints in synthetic processes used in the creation of this compound) alpha configured; which is not the usual, most prevalent, conformation favored for the PT cocaine-receptor binding pocket of most such sub-type of chemicals. The above and below depictions show attested compounds synthesized, additionally with variations upon the Endo–exo isomerism of their structures.^[40]

3-Phenyl-9-azabicyclo[3.3.1]nonane derivatives

To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs.^[i] Which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol.

Despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. Though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. Instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below.

3-Phenyl-7-azabicyclo[2.2.1]heptane derivatives

Ring-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on MAT for an affinity in the efficacious range. The distance from the nitrogen to the phenyl centroid for 155a was 4.2 and 155c was 5.0 Å, respectively. (Whereas troparil was 5.6 & compound 20a 5.5 angstroms). However piperidine homologues (discussed below) had comparable potencies.^[j]

Azabornanes with longer substitutions at the 3β-position (benzoyloxys alkylphenyls, carbamoyls etc.) or with the nitrogen in the position it would be on the piperidine homologues (i.e. arrangements of differing locations for the nitrogens being either distal or proximal within the terms required to facilitate the framework of the compound to a correlative proportion, functional for the given moiety), were not synthesized, despite conclusions that the nitrogen to phenyl length was the issue at variance enough to be the interfering factor for the proper binding of the compressed topology of the azabornane. Carroll, however, has listed benzoyloxy azabornanes in patents.^[3]

Piperidine homologues had comparable affinity & potency spreads to their respective phenyltropane analogues. Without as much of a discrepancy between the differing isomers of the piperidine class with respect to affinity and binding values as had in the phenyltropanes.

Heterocyclic N-Desmethyl^[43]

cf. Fencamfamine

These compounds include transition metals in their heteroatomic conformation, unlike non-radiolabel intended chelates where their element is chosen for intrinsic affectation to binding and function, these are tagged on by a "tail" (or similar) with a sufficient spacer to remain separated from known binding properties and instead are meant to add radioactivity enough to be easily tracked via observation methods that utilize radioactivity. As for anomalies of binding within the spectrum of the under-written kinds just mentioned: other factors not otherwise considered to account for its relatively lower potency, "compound 89c" is posited to protrude forward at the aryl place on its moiety toward the MAT ligand acceptor site in a manner detrimental to its efficacy. That is considered due to the steric bulk of the eight-position "tail" chelate substituted constituent, overreaching the means by which it was intended to be isolated from binding factors upon a tail, and ultimately nonetheless, interfering with its ability to bind. However, to broach this discrepancy, decreasing of the nitrogen tether at the eight position by a single methylene unit (89d) was shown to bring the potency of the analogous compound to the expected, substantially higher, potency: The N-methyl analog of 89c having an IC₅₀ of 1.09 ± 0.02 @ DAT & 2.47 ± 0.14 nM @ SERT; making 89c upwards of thirty-three times weaker at those MAT uptake sites.^[k]

• ^ɑIUPAC: [2-[[2-[[[3-(4-chlorophenyl)-7-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl]-(2-mercaptoethyl)amino]ethyl]amino]ethanethiolato-(3—)-N2, N2′, S2, S2′]oxo-[1''R''-(''exo'', ''exo'')]-[99mTc]technetium
• ^bR- & S- isomer values are K_i (nM) for displacement of [¹²⁵I]IPT with technetium-99m replaced by rhenium
• ^cIC₅₀ (nM) values for displacement of [³H]WIN 35428 with ligand tricarbonyltechnetium replaced with rhenium. (IC₅₀ for WIN 35428 were 2.62 ± 1.06 @ high affinity binding & 139 ± 72 @ low affinity binding sites)
• ^dK_i value for displacement of [¹²⁵I]IPT radioligand.

Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.
Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. U.S. patent 6,329,520, U.S. patent 7,011,813, U.S. patent 6,531,483, and U.S. patent 7,291,737.

Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug that is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT binding affinity.

Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine class (a category that includes methylphenidate) or benztropine class (such as Difluoropine: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.

Most any variant with a tropane locant—3-β (or α) connecting linkage differing from, e.g. longer than, a single methylene unit (i.e. "phenyl"), including alkylphenyls (see the styrene analog, first image given in example below) is more correctly a "cocaine analogue" proper, and not a phenyltropane. Especially if this linkage imparts a sodium channel blocker functionality to the molecule.

• List of cocaine analogues
  • List of local anesthetics
• List of methylphenidate analogues

• 研究で将来使用されるトロパン化合物の例を列挙した米国仮特許出願
• コカイン類似体研究に関する記事 2006-09-22 にWayback Machineにアーカイブ