Phenyltropanes (PTs) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; and thusly the phenyl is attached direct to the tropane skeleton with no further spacer (therefore the name "phenyl"-tropane) that the cocaine benzoyloxy provided. The original purpose of which was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (since the methylated benzoate ester is essential to cocaine's blockage of sodium channels which cause topical anesthesia) while retaining stimulant function. These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's & Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.) Certain phenyltropanes can even be used as a smoking cessation aid (c.f. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers (in this case the long form is either RTI-COC-n, for 'cocaine' "analog", or specifically RTI-4229-n of the subsequent numbers given below in this article) Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.
2-Carboxymethyl esters (phenyl-methylecgonines)
Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.
Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact. The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.
Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.
(4′-Monosubstituted 2,3-Thiophene phenyl)-tropanes
(3′,4′-Disubstituted phenyl)-tropanes
ɑas ·HCl (salt) bas ·HCl·2 H2O (salt) cSingh gives the reverse value with respect to i.e. 1,329 for NET & 320 for 5-HT { | class="wikitable sortable" |+Para-meta-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes ! Compound ! Short Name(S. Singh) ! R2 ! R1 ! DA ! 5HT ! NE ! Selectivity5-HTT/DAT ! SelectivityNET/DAT |- | ||meta-fluorophenyltropane16a || F || H ||23 ± 7.8||-||-||-||- |- | ||meta-chlorophenyltropane16b || Cl || H ||10.6 ± 1.8||-||-||-||- |- | ||meta-bromophenyltropane16c|| Br || H ||7.93 ± 0.08ɑ||-||-||-||- |- | |||meta-iodophenyltropane16d|| I || H ||26.1 ± 1.7||-||-||-||- |- | ||meta-tributylstannylphenyltropane16e || SnBu3|| H ||1100 ± 170||-||-||-||- |- | ||meta-ethynylphenyltropane||C≡CH||H||-||-||-||-||- |- | ||meta-methyl-para-fluorophenyltropaneRTI-9617a || CH3 || F ||2.95 ± 0.58||-||-||-||- |- | ||meta-methyl-para-chlorophenyltropaneRTI-112c17b || CH3 || Cl ||0.81 ± 0.05||10.5 ± 0.05||36.2 ± 1.0||13.0||44.7 |- | ||meta-para-dichlorophenyltropaneRTI-111b Dichloropane17c || Cl || Cl ||0.79 ± 0.08b||3.13 ± 0.36b||18.0 ± 0.817.96 ± 0.85<sup>b'd</sup>||4.0b||22.8b |- | ||meta-bromo-para-aminophenyltropaneRTI-9717d || Br || NH2 ||3.91 ± 0.59||181||282||46.2||72.1 |- | ||meta-iodo-para-aminophenyltropaneRTI-8817e || I || NH2 ||1.35 ± 0.11||120 ± 4||1329 ± 124||88.9||984 |- | ||meta-iodo-para-azidophenyltropane17f|| I || N3 ||4.93 ± 0.32||-||-||-||- |} ɑIC50 determined in Cynomolgous monkey caudate-putamen bas ·HCl (salt) cas ·HCl·2 H2O (salt) dNEN