Chemistry and Structure-Activity Relationships of Mecamylamine and Derivatives

Stone, Clement A.; Torchiana, Mary Lou; Stavorski, John M.; Sletzinger, M.; Stein, Gustav A.; Ruyle, William V.; Reinhold, Donald F.; Gaines, Walter A.; Arnold, Heinz.; Pfister, Karl

doi:10.1021/jm01239a001

Cited by 28 publications

(20 citation statements)

References 10 publications

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“…Reduction with lithium aluminium hydride gave mecamylamine (30). 87 Thus, a methyl group was optimal. 95 Structure-activity relationship (SAR) studies indicated that alkylating the amine increased activity, but activity decreased as the size of the alkyl substituent was increased.…”

Section: Mecamylaminementioning

confidence: 99%

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Pharmaceuticals that contain polycyclic hydrocarbon scaffolds

2015

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Numerous variations on structural motifs exist within pharmaceutical compounds that have entered the clinic. These variations have amounted over many decades based on years of drug development associated with screening natural products and de novo synthetic systems. Caged (or bridged) bicyclic structural elements offer a variety of diverse features, encompassing three-dimensional shape, and assorted pharmacokinetic properties. This review highlights approximately 20 all carbon cage containing pharmaceuticals, ranging in structure from bicyclo[2.2.1] through to adamantane, including some in the top-selling pharmaceutical bracket. Although, a wide variety of human diseases, illnesses and conditions are treated with drugs containing the bicyclic motif, a common feature is that many of these lipophilic systems display CNS and/or neurological activity. In addition, to an extensive overview of the history and biology associated with each drug, a survey of synthetic methods used to construct these entities is presented. An analysis section compares natural products to synthetics in drug discovery, and entertains the classical caged hydrocarbon systems potentially missing from the clinic. Lastly, this unprecedented review is highly pertinent at a time when big pharma is desperately trying to escape flatland drugs.

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Section: Mecamylaminementioning

confidence: 99%

“…Enantiomerically pure mecamylamine can be obtained by resolving racemic mecamylamine, using D-camphorsulfonic acid in acetone (Scheme 5), or can be synthesized directly from D-camphene. 87 87 Thus, a methyl group was optimal.…”

Section: Mecamylaminementioning

confidence: 99%

Pharmaceuticals that contain polycyclic hydrocarbon scaffolds

2015

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“…Examination of the pharmacological properties of the mecamylamine stereoisomers (Fig. 1) began soon after the racemate was developed (Stone et al, 1962). Suchocki and colleagues (1991), using a mouse model, found no difference in potency between racemic mecamylamine, S(+)-mecamylamine or R(−)-mecamylamine with respect to inhibition of nicotine-induced decreases in spontaneous activity and antinociceptive effects.…”

Section: 0 Neuropharmacologymentioning

confidence: 99%

Potential therapeutic uses of mecamylamine and its stereoisomers

Nickell

Grinevich

Siripurapu

et al. 2013

Pharmacology Biochemistry and Behavior

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Mecamylamine (3-methylaminoisocamphane hydrochloride) is a nicotinic parasympathetic ganglionic blocker, originally utilized as a therapeutic agent to treat hypertension. Mecamylamine administration produces several deleterious side-effects at therapeutically relevant doses. As such, mecamylamine’s use as an antihypertensive agent was phased out, except in severe hypertension. Mecamylamine easily traverses the blood-brain barrier to reach the central nervous system (CNS), where it acts as a nicotinic acetylcholine receptor (nAChR) antagonist, inhibiting all known nAChR subtypes. Since nAChRs play a major role in numerous physiological and pathological processes, it is not surprising that mecamylamine has been evaluated for its potential therapeutic effects in a wide variety of CNS disorders, including addiction. Importantly, mecamylamine produces its therapeutic effects on the CNS at doses 3-fold lower than those used to treat hypertension, which diminishes the probability of peripheral side-effects. This review focuses on the pharmacological properties of mecamylamine, the differential effects of its stereoisomers, S(+)- and R(−)-mecamylamine, and the potential for effectiveness in treating CNS disorders, including nicotine and alcohol addiction, mood disorders, cognitive impairment and attention deficit hyperactivity disorder.

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“…for CI,H2,BrN02 (352.25): C 57.96,H 6.29,N 6.29; found: C 5X.04, H 6.35, N 3.93. *) IUPAC name of (1 S)-1,2,3,4-tetrahydroharine: (1 S)-1,2,3,4-tetrahydro-7-methoxy-l -methyl-1 H-pyrido- [3,44]indol ((-)-18).…”

Section: (Ls]-1234-tetruh~~drohurmine ((-)-Is)mentioning

confidence: 99%

“…~ Chemical resolution of racemic amines with optically active acids is the method most widely used to prepare optical isomers and frequently has been applied to prepare alkaloids of unnatural configuration (many examples of successful chemical resolutions are reported in [lb]). Racemic-amine drugs such as mefloquine [2] and mecamylamine [3] have been resolved in an analogous fashion and studied as optical isomers. However, there are cases where chemical resolution proved difficult or afforded the desired optical isomer only after tedious crystallization of salts, resulting in low yield of optically pure material.…”

mentioning

confidence: 99%

Fragmentation of Optically Active (1‐Phenylethyl)‐ and (1‐Naphthylethyl)ureas in Refluxing Alcohols: Easy Preparation of Optically Active Amines of High Optical Purity

Schönenberger

Brossi

1986

Helvetica Chimica Acta

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I-Phenylethy1)-and (1 -iiaphthylethyl)ureas, obtained in the reaction of racemic amines with optically pure isocyanates, are separated and then decomposed in refluxing alcohols, to afford optically pure secondary amines and optically pure alkyl carbamates in quantitative yields. The scope of this fragmentation for the resolution of racemic mixtures of amines is illustrated by several examples of biologically important compounds. Carbamates obtained by this fragmentation can readily be recycled.(S)-5a having identical optical properties was prepared from amine (S)-6a and ethyl chloroformate [ 151. Scheme I also lists carbamates obtained in reactions described later. Reaction of 3 in refluxing propanol without addition of base also afforded (+)-mecamylamine ((+)-I), but at a slower rate.Reductive ring closure of oxindole (&)-7, prepared by the Juliun synthesis [4], was best accomplished with Na in EtOH and afforded 5-0-methyl-I-noreseroline ((f)-8; Scheme 2). Reaction of (f)-8 with isocyanate (S)-2a afforded after chromatographic separation of the mixture of diastereoisomers, the less polar urea 9 and the more polar urea 10 in 37 and 40% yield, respectively. Ureas 9 and 10 decomposed in refluxing 1~ sodium pentoxide in pentanol within 1 h, affording as basic materials the optically pure amines (+)- (non-crystalline) (+)-13 16En3 o CH,

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Chemistry and Structure-Activity Relationships of Mecamylamine and Derivatives

Cited by 28 publications

References 10 publications

Pharmaceuticals that contain polycyclic hydrocarbon scaffolds

Pharmaceuticals that contain polycyclic hydrocarbon scaffolds

Potential therapeutic uses of mecamylamine and its stereoisomers

Fragmentation of Optically Active (1‐Phenylethyl)‐ and (1‐Naphthylethyl)ureas in Refluxing Alcohols: Easy Preparation of Optically Active Amines of High Optical Purity

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