Aryl-cycloalkyl-alkanolamines for treatment of epilepsy

A compound and method are disclosed for reducing the effects of epilepsy, especially temporal lobe epilepsy. The treatment disclosed by the subject invention is provided by administering an aryl-cycloalkyl-alkanolamine substance having the general formula: ##STR1## The compounds procyclidine, biperiden, and trihexyphenidyl fall within this class of compounds. Although not previously recognized to be effective against epilepsy, all three representative compounds were tested against soman and pilocarpine, two cholinergic neurotoxins used in animal research on epilepsy. All three of those compounds were shown to be highly effective in providing protection against the seizures and neurological damage caused by cholinergic neurotoxins, even when administered only after the onset of convulsions.

FIELD OF THE INVENTION 
This invention is in the fields of pharmacology and neurology. It relates 
specifically to compounds and methods for preventing or suppressing 
epileptic seizures and for protecting against brain damage associated with 
severe epilepsy. 
BACKGROUND OF THE INVENTION 
A pattern of brain damage is often found at autopsy in individuals whose 
clinical history includes frequent episodes of prolonged epileptic 
seizures (Corsellis et al 1976; a list of complete citations is provided 
below). Such epilepsy-related brain damage occurs most frequently in 
association with a type of epilepsy known as temporal lobe epilepsy (also 
referred to as psychomotor epilepsy or complex partial seizures). In this 
type of epilepsy, episodes of seizure activity may be quite prolonged 
(i.e., they may last for several hours), and they are often very difficult 
to control with any drugs currently available. The mechanism by which 
prolonged seizures give rise to brain damage was unknown until recent 
animal studies provided evidence linking such damage to excitatory 
transmitter systems in the brain, primarily the glutamate transmitter 
system (Olney et al 1986). 
It is impossible to demonstrate with certainty that any seizure or 
seizure-related brain damage in a non-human animal falls within the proper 
definition of "epilepsy." Therefore, seizures and brain damage in lab 
animals which appear to be comparable to human epilepsy are referred to as 
"epileptiform" rather than "epilepsy." In lab animals, epileptiform 
seizures and brain damage can be induced by convulsant drugs, as discussed 
below. They also occur spontaneously in some strains of lab animals which 
are specially bred to exhibit epileptiform symptoms. Despite limitations, 
animal models offer the only methods available to researchers for studying 
epilepsy, short of tests on humans. Therefore, researchers use animal 
models to test drugs for anti-convulsant potential, and a great deal of 
research has been devoted to identifying drugs which generate epileptiform 
manifestations (i.e., seizure activity) and consequences (particular types 
of brain damage) that most closely resemble the manifestations and 
consequences of epilepsy in humans. 
Three of the convulsant drugs that are of interest to researchers studying 
epilepsy are (1) kainic acid, a glutamate agonist (Nadler 1981); (2) 
pilocarpine, a cholinergic agonist (Clifford et al 1987); and (3) soman, a 
cholinesterase inhibitor (McLeod et al 1984). In several important 
respects, both the manifestations and the consequences of severe cases of 
epilepsy, especially temporal lobe epilepsy, resemble the manifestations 
and consequences of each of those convulsant drugs. Each of those 
substances can cause continuous seizure activity which can persist for 
hours, similar to "status epilepticus" in humans. In addition, each of 
those substances causes disseminated brain damage which resembles the 
damage observed during autopsies of humans who suffered from severe 
epilepsy. 
A number of efforts to treat lab animals against convulsions induced by 
kainic acid, pilocarpine, and soman have focused on tranquilizers and 
sedatives. Diazepam (sold under the trade name Valium) suppresses seizures 
induced by these agents, but only at relatively high doses which are 
overly sedating (Clifford et al 1982; Fuller et al 1981). This makes such 
agents undesirable, especially as a long-term preventive measure. 
Braitman et al 1988 states that a substance referred to as MK-801 (a 
glutamate antagonist, discussed below) provides some degree of protection 
against soman, if administered before soman exposure and if used in 
conjunction with other protective agents. However, recent research by the 
inventor of the subject application has discovered that when MK-801, 
phencyclidine, or ketamine were used in an effort to protect lab animals 
against pilocarpine, the seizure activity was made worse and the outcome 
was rapidly lethal. Although the reasons for these apparently conflicting 
results are not entirely clear, both sets of results suggest that 
interactions between the cholinergic and glutamate receptor systems may be 
relevant to efforts to provide an effective method for protecting the 
brain against epileptic seizures and against brain damage which can result 
from such seizures. The following sections provide information on both the 
cholinergic and glutamate receptor systems. 
Receptors, messenger molecules, agonists, and antagonists 
The surfaces of nerve cells in the brain contain various types of receptor 
molecules. In general, a receptor molecule is a polypeptide which 
straddles a cell membrane. When a messenger molecule interacts with the 
exposed extracellular portion of the membrane receptor molecule, it 
triggers a difference in the electrochemical status of the intracellular 
portion of the receptor, which in turn provokes some response by the cell. 
The messenger molecule does not bond to the receptor; instead, it usually 
disengages from the receptor after a brief period and returns to the 
extracellular fluid. Most receptor molecules are named according to the 
messenger molecules which bind to them. 
An "agonist" is any molecule, including the naturally occurring messenger 
molecule, which can temporarily bind to and activate a certain type of 
receptor. An agonist can cause the same effect as the natural messenger 
molecule, or in some cases it can cause a more intense effect (for 
example, if it has a tighter affinity for the receptor molecule and 
remains bound to the receptor for a prolonged period). 
By contrast, an "antagonist" is a molecule which can block or reduce the 
effects exerted by the natural messenger molecule. This can happen in 
several different ways. A "competitive antagonist" binds to a certain type 
of receptor without triggering it, thereby preventing the natural 
messenger molecule from reaching and activating the receptor. A 
"non-competitive antagonist" functions in other ways. For example, a 
receptor referred to as the PCP receptor, which is triggered by molecules 
such as PCP or MK-801, apparently can override the effects of a different 
type of receptor, the NMDA receptor (both receptors are discussed below). 
Therefore, PCP and MK-801 are regarded as non-competitive antagonists for 
the NMDA receptor. 
Whether a given molecule is classified as an agonist or antagonist depends 
on the receptor context. For example, while MK-801 is an antagonist for 
the NMDA receptor, it is an agonist for the PCP receptor. Most agonists 
and antagonists are xenobiotic drugs, i.e., they do not exist naturally in 
the body. 
For more information on neurotransmitters, receptors in the brain and 
central nervous system, and agonists and antagonists which interact with 
brain cell receptors, see Adelman 1987. 
The two classes of excitatory receptor molecules that are of interest with 
respect to the subject invention are referred to as "cholinergic" 
receptors and "glutamate" (also called "EAA") receptors, discussed below. 
Both types of receptors are present in the synaptic junctions that serve 
as pathways for impulses between nerve cells in the brain. They are 
believed to be the two main classes of excitatory receptors. Most other 
types of receptors in the brain involve inhibitory neurotransmitters. 
Cholinergic receptors 
Cholinergic receptors are activated by acetyl choline, a relatively small 
molecule released by certain types of brain cells. Cholinergic receptors 
are divided into two main classes: the muscarinic receptors (which are 
further subdivided into M1 and M2 receptors), and the nicotinic receptors. 
After a molecule of acetyl choline performs its neurotransmitter function, 
it is quickly degraded by an enzyme called cholinesterase. Some types of 
toxins, including the nerve gas soman and some types of insecticides, 
generate toxic effects by inhibiting the cholinesterase enzyme. If that 
enzyme is disabled, an excess of acetyl choline accumulates in the 
extracellular fluid, where it causes uncontrolled firing of the nerve 
cells and results in severe neural damage, typically ending in death. 
Pilocarpine acts in a different manner, as an agonist at cholinergic 
receptors. It can cause a severe syndrome consisting of continuous 
"clonic" seizure activity (seizure activity manifested by shaking; a 
"tonic" seizure is manifested by muscle rigidity) that often terminates in 
death. After an hour of such seizure activity, acute neuronal degeneration 
is evident (Clifford et al 1987). A high dose of pilocarpine (400 mg/kg 
subcutaneously) is usually required to cause this syndrome, and rats show 
considerable individual variability in sensitivity. However, it is 
possible to produce this cholinotoxic syndrome consistently with a low 
dose of pilocarpine (30 mg/kg) if it is preceded by a priming dose of 
lithium (Honchar et al 1983). Therefore, the lithium/pilocarpine syndrome 
has become a useful animal model for studying cholinergic neurotoxic 
mechanisms and seizure-related brain damage. 
Glutamate receptors 
Glutamic acid and aspartic acid are amino acids. Each contains two 
carboxylic acid groups. Either of those amino acids, and various analogs 
of those molecules, can trigger a class of receptors referred to as 
"excitatory amino acid" (EAA) receptors. 
EAA receptors are also referred to as "glutamate" receptors, for several 
reasons. At the normal pH which exists in the brain, glutamic acid 
dissociates to form its ion, glutamate, which is naturally present in high 
concentrations inside the brain cells. Glutamate was the first molecule 
shown to trigger EAA receptors, and glutamate has been shown to trigger 
all three known subtypes of EAA receptors. It is suspected of being the 
natural transmitter at all EAA receptors. 
There are three known types of glutamate receptors. One type is called the 
kainic acid (KA) receptor, since it can be triggered (in lab conditions) 
by kainic acid, a glutamate agonist which normally does not exist inside 
the brain. As mentioned above, kainic acid, a potent convulsant, is used 
in lab animals to study the mechanisms of epileptic seizures and 
epilepsy-related brain damage. 
Another type of glutamate receptor is called the quisqualate (QUIS) 
receptor, since it can be triggered by quisqualic acid, another convulsant 
drug. 
The third known type of glutamate receptor is called the NMDA receptor. The 
molecule N-methyl aspartate (NMA) is an analog of glutamate. Like all 
amino acids except glycine, it exists in two different isomers, the D and 
L forms. The D isomer of NMA--referred to as NMDA--exerts a powerful 
agonist effect on some glutamate receptors. Therefore, those receptors are 
referred to as NMDA receptors. 
Each type of glutamate receptor controls a set of ion channel. For example, 
when an NMDA receptor is triggered by a glutamate molecule or a related 
agonist, it opens an ion channel which causes sodium and calcium to enter 
the cell while potassium is transported out of the cell. 
Some molecules block the effects of glutamate on NMDA receptors, but they 
apparently do not act by directly blocking or occupying NMDA receptors; 
instead, they appear to activate other receptors (PCP receptors) which 
block the opening of the NMDA-receptor-controlled ion channels. In effect, 
they override the effects of the NMDA receptors, acting as 
"non-competitive antagonists." Such molecules include phencyclidine (PCP) 
and ketamine (see Anis et al 1983), and various phencyclidine derivatives 
(Berry et al 1983). Phencyclidine and ketamine reduce the excitatory 
effects of NMDA receptors, while they have no direct effect on the ion 
channels controlled by KA and QUIS receptors (Anis 1983). 
The drug {(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine 
maleate)}, commonly referred to as MK-801, is also a non-competitive 
antagonist of the NMDA receptor site (Wong 1986). It is a highly 
competitive agonist for the PCP receptor. 
PCP, ketamine, and MK-801 are of interest because they can cross the 
blood-brain barrier and reach brain cells. Other NMDA antagonists such as 
D-.alpha.-amino-5-phosphonopentanoate are also glutamate antagonists; 
however, since they cannot cross the blood-brain barrier, they are of 
little interest to neurologists. 
Glutamate neurotoxicity 
Glutamate normally exists at relatively high concentration (roughly 10 
millimolar (mM)) inside axons. It is released by axon terminals very 
sparsely and in a very controlled manner, so that it directly enters a 
synaptic cleft and contacts a synaptic glutamate receptor. The only known 
mechanism for terminating the excitatory action of glutamate is to remove 
it from the synaptic cleft. This is normally achieved by energy-dependent 
transport systems that transport the extra-cellular glutamate back inside 
the axon terminals. 
Certain types of low energy conditions can impair the ability of the 
glutamate transport system to control the amount of extracellular 
glutamate. Such conditions can include hypoglycemia (low blood sugar), 
ischemia (reduced blood flow, such as caused by stroke or heart attack), 
and hypoxia (low oxygen levels, caused by problems such as severe anemia, 
hemoglobin defects, carbon monoxide poisoning, and asphyxia). Under those 
conditions, brain cells release glutamate and, because of the energy 
deficiency, the transport systems are unable to move the glutamate back 
into the cells at an adequate rate. When present in abnormal 
concentrations in the extracellular fluid, glutamate is in continuous 
contact with and hyper-stimulates its receptors. This can cause 
"excitotoxic" degeneration of nerve cells bearing such receptors. 
"Excitotoxic" is a term referring to the specific type of excitatory 
neurotoxicity that glutamate or related EAA's possess (Olney et al 1983). 
This problem can be severely aggravated by the fact that initial glutamate 
release can stimulate further release of glutamate, which results in a 
cascade of extracellular glutamate accumulation and neurotoxic injury. It 
is believed that some of the neurotoxic injury associated with hypoxia or 
ischemia involves the action of glutamate at NMDA receptors, since such 
injury can be reduced or prevented by administering NMDA antagonists such 
as PCP, ketamine, and MK-801 (Lawrence et al 1987; Olney et al 1989). 
It is also believed that in either the pilocarpine or soman cholinotoxic 
syndromes, persistent seizure activity is triggered by the excitatory 
activation of muscarinic cholinergic receptors, but much of the brain 
damage which ensues may be caused by seizure-mediated release of excessive 
glutamate at NMDA receptors. However, when NMDA antagonists such as 
phencyclidine, MK-801 or ketamine, which protect the brain against damage 
associated with kainic acid-induced seizures (Labruyere et al 1986), were 
administered to lithium/pilocarpine-treated rats by the inventor of the 
subject invention, a reaction was seen in which the seizure activity was 
made worse and the outcome was rapidly lethal. This unexpected finding 
suggests that an unknown mechanism operates in which phencyclidine, 
ketamine, or MK-801 interact with the cholinergic transmitter system to 
potentiate cholinergic activity. 
Another potential disadvantage of using PCP, ketamine, or MK-801 for 
protecting against seizure-related neuropathology is that phencyclidine, 
the prototypic compound in this class, induces psychotomimetic effects in 
humans (Goodman et al 1975). Moreover, the inventor of the subject 
invention has recently discovered that phencyclidine, MK-801 and ketamine 
induce a neurodegenerative reaction in the posterior cingulate and 
retrosplenial cerebral cortex when administered in relatively low doses to 
adult rats (Olney et al 1989). 
Prior to this invention, there has been no effective way for protecting 
mammals (including humans) against cholinergic neurotoxins such as soman 
or pilocarpine. The subject invention provides the most effective and 
reliable method discovered to date for treating mammals against those 
convulsant drugs. Because the effects of these convulsants are similar to 
the effects of certain types of epilepsy, in terms of both seizure 
activity and histological brain damage, there is a strong indication that 
an agent which can provide useful and effective protection against soman 
and pilocarpine may also be capable of providing at least some degree of 
protection against at least some types of epilepsy which have previously 
been regarded as intractable. 
Aryl-cycloalkyl-alkanolamine compounds 
Several aryl-cycloalkyl-alkanolamine drugs, including procyclidine, 
biperiden, and trihexyphenidyl, are known to have anti-cholinergic actions 
and have been identified for treatment of Parkinson's disease. Such 
compounds ameliorate the muscle rigidity and akinesia associated with 
Parkinsonism and extrapyramidal symptoms associated with neuroleptic drug 
treatment (Goodman et al 1975). 
Some of these compounds have also been shown to have some degree of NMDA 
receptor antagonist properties, in that they reduce NMDA-induced neuronal 
degeneration in isolated chick embryo retinas (Olney et al 1987). Although 
these agents apparently compete with phencyclidine receptor ligands for 
binding at the PCP receptor, they are quite weak in PCP receptor activity 
compared to phencyclidine receptor ligands such as phencyclidine itself 
and MK-801. 
The compound .alpha.-cyclohexyl-.alpha.-phenyl-1-pyrrolidinepropanol, 
commonly known as procyclidine, is described in U.S. Pat. No. 2,891,890 
(Adamson 1959) as an anti-Parkinsonian drug. It is marketed under the 
trade name Kemadrin by Burroughs-Wellcome. 
The compound commonly known as biperiden, 
.alpha.-bicyclo[2.2.1]-hept-5-en-2-yl-.alpha.-phenyl-1-piperidine-propanol 
, has been studied for its mood altering effects (Fleischhacker et al 1987) 
and for its interaction with brain muscarinic cholinoceptors (Syvalahti et 
al 1987). The hydrochloride salt of biperiden has been studied for its 
interaction with nicotine and oxotremorine in rat diaphragm (Das et al 
1977). Biperiden is marketed under the trade name "Akineton" by Knoll. 
The compound 
.alpha.-phenyl-.alpha.-tricyclo[2.2.1.02,6]-hept-3-yl-1-piperidinepropanol 
, commonly known as triperiden, is an anti-Parkinsonism agent which also 
reportedly has anti-viral properties (Schroeder et al 1985). It is 
marketed in Europe under the trade name "Norakin" by VEB Fahlberg-List 
(Magdeburg, West Germany). 
The compound .alpha.-cyclohexyl-.alpha.-phenyl-1-piperidinepropanol, 
commonly known as trihexyphenidyl, is a known anti-Parkinsonian which has 
been studied for its effects in schizophrenic patients (Hitri et al 1987) 
and for its effects on memory in elderly patients McEvoy et al 1987). It 
is marketed under the trade name "Artane" by Lederle. 
Various other aryl-cycloalkyl-alkanolamine compounds have also been studied 
for varying purposes. For example, U.S. Pat. No. 4,031,245 mentions the 
compound 
.alpha.-cyclopropyl-.alpha.-[3-(trifluoromethyl)phenyl]-1-piperidinepropan 
ol and its hydrochloride derivative in a description of alkenyl and 
alkanylamines for treating depression. U.S. Pat. No. 3,553,225 mentions 
the compound 
.alpha.-phenyl-.alpha.-tricyclo[3.3.1.13,7]-dec-1-yl-1-piperidine-butanol 
in a description of adamantane derivatives as tranquilizers West German 
Offen. No. 1, 951,614, in a description of benzyl alcohol derivatives 
having sedative and ulcer-preventing properties, mentions the compounds 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-cyclohexyl-1-piperidinebutanol 
, .alpha.-(4-amino-3-chlorophenyl)-.alpha.-cyclo-hexylhexahydro-1H-azepine- 
1-butanol, 
.alpha.-(4-amino-3,5-dichlorophenyl)-.alpha.-cyclohexahydro-1H-azepine-1-b 
utanol, and .alpha.-(4-amino-3,5-dibromopheny 
.alpha.-cyclohexyl-1,8,8-trimethyl-3-azabicyclo[3,2,1]octane-3-butanol. 
The compound .alpha.-[1,1'-biphenyl]-4-yl-.alpha.-cyclohexyl-1-piperidine 
propanol hydrochloride was mentioned in a study of the potential analgetic 
activity of some reduced biphenyl Mannich bases (Mann et al 1976). 
It has not been proposed that any of these drugs could or should be useful 
either in animals or humans as a treatment to prevent epileptic seizures 
or seizure-related brain damage. Prior to this invention, there has been 
no adequate method or pharmacological agent for preventing or controlling 
seizures caused by temporal lobe epilepsy, or for minimizing brain damage 
suffered from such seizures. 
SUMMARY OF THE INVENTION 
A compound and method are disclosed for reducing the effects of epilepsy, 
especially temporal lobe epilepsy. The treatment disclosed by the subject 
invention is provided by administering an aryl-cycloalkyl-alkanolamine 
substance having the general formula: 
##STR2## 
The compounds procyclidine, biperiden, and trihexyphenidyl fall within this 
class of compounds. Although not previously recognized to be effective 
against epilepsy, all three representative compounds were tested against 
soman and pilocarpine, two cholinergic neurotoxins used in animal research 
on epilepsy. All three of those compounds were shown to be highly 
effective in providing protection against the seizures and neurological 
damage caused by cholinergic neurotoxins, even when administered only 
after the onset of convulsions.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
This invention relates to a compound and method for reducing the effects of 
epilepsy. As used herein, the effects of epilepsy include (1) 
manifestations such as seizure activity, and/or (2) consequences such as 
neurological or brain damage, which are associated with one or more types 
of epilepsy. 
The treatment disclosed by this invention can be provided by administering 
to a susceptible mammal an aryl-cycloalkylalkanolamine represented by 
Formula I: 
##STR3## 
wherein R.sup.1 is one or more groups independently selected from hydrido, 
halo, alkyl, acyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, amino, 
alkylamino and acylamino; wherein R.sup.2 is selected from hydrido, 
cycloalkyl, cycloalkenyl, halocycloalkyl, alkylcycloalkyl, acylcycloalkyl, 
hydroxycycloalkyl, haloalkylcycloalkyl, aminoalkylcycloalkyl, 
alkoxycycloalkyl, aminocycloalkyl, bicycloalkyl, bicycloalkenyl and 
tricycloalkyl wherein the bicycloalkyl, bicycloalkenyl and tricycloalkyl 
groups may be substituted with one or more groups selected from alkyl, 
halo, acyl, hydroxy, hydroxyalkyl, haloalkyl, acyl, alkoxy, amino and 
alkylamino; wherein each of R.sup.3 and R.sup.4 is independently selected 
from hydrido, alkyl, acyl, alkenyl, cycloalkyl, phenylalkyl, phenyl, 
aminoalkyl and alkylaminoalkyl; and wherein R.sup.3 and R.sup.4 may be 
taken together to form a cyclic group including the nitrogen atom of 
Formula I, and n is an integer selected from one through five. 
Several compounds covered by Formula I are commercially available, 
including: 
.alpha.-cyclohexyl-.alpha.-phenyl-1-pyrrolidinepropanol (common name 
"procyclidine"), which has the following structure: 
##STR4## 
.alpha.-cyclohexyl-.alpha.-phenyl-1-piperidinepropanol (common name 
"trihexyphenidyl"), which has the following structure: 
##STR5## 
.alpha.-bicyclo[2.2.1]hept-5-en-2-yl-.alpha.-phenyl-1-piperidinepropanol 
(common name "biperiden"), which has the following structure: 
##STR6## 
.alpha.-phenyl-.alpha.-tircyclo [2.2.1.02,6]hept-3-yl-1-piperidinepropanol 
(common name "triperiden") which has the following structure: 
##STR7## 
The following compounds also have chemical structures within the parameters 
described in Formula I: 
3,3,5-trimethyl-.alpha.-phenyl-.alpha.-[2-(1-piperidinyl)ethylcyclohexaneme 
thanol; 
4-hydroxy-.alpha.-4-diphenyl-.alpha.-tricyclo[2.2.1.02,6]hept-1-yl-1-piperi 
dinepropanol; 
.alpha.-cyclopropyl-.alpha.-[3-(trifluoromethyl)phenyl]-1-piperidinepropano 
l 
.alpha.-phenyl-.alpha.-tricyclo[3.3.1.13,7]dec-1-yl-1-piperidinebutanol; 
.alpha.-phenyl-.alpha.-tricyclo[2.2.1.02,6]hept-3-yl-1-piperidinepropanol 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-cyclohexyl-1-piperidinebutanol; 
.alpha.-(p-chlorophenyl)-.alpha.-cyclohexyl-1-piperidinepropanol 
.alpha.-(4-amino-3-chlorophenyl)-.alpha.-cyclohexylhexahydro-1H-azepine-1-b 
utanol; 
.alpha.-cyclohexyl-.alpha.-(p-methoxyphenyl)-1-piperidinepropanol; 
.alpha.-(4-amino-3,5-dichlorophenyl)-.alpha.-cyclohexylhexahydro-1H-azepine 
-1-butanol; 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-cyclohexyl-1,8,8-trimethyl-3-az 
abicyclo[3.2.1]octane -3-butanol; 
.alpha.-[1,1'-biphenyl]-4-yl-.alpha.-cyclohexyl-1-piperidine-propanol; 
.alpha.-phenyl-.alpha.-tricyclo[3.3.1.13,7]dec-1-yl-1-pyrrolidinepropanol 
.alpha.-(3,3-dimethylbicyclo[2.2.1]hept-2-yl)-.alpha.-phenyl-1-piperidinepr 
opanol; 
.alpha.-cyclohexyl-4-hydroxy-.alpha.-4-diphenyl-1-piperidinepropanol 
.alpha.-cyclopropyl-.alpha.-[3-(trifluoromethyl)phenyl]-1-piperidinepropano 
l; 
.alpha.-cyclohexyl-.alpha.-phenyl-3-azabicyclo[3.2.2]nonane-3-propanol 
.alpha.-[2-(diethylamino)ethyl]-.alpha.-phenylcyclohexanemethanol; 
.alpha.-cyclopentyl-.alpha.-(3-(dimethylaminopropyl]-p-methoxybenzyl 
alcohol; 
.alpha.-[3-(dimethylamino)propyl]-.alpha.-(.alpha.,.alpha.,.alpha.-trifluor 
o-m-tolyl)-cyclohexanemethanol; 
.alpha.-[3-(dimethylamino)propyl]-.alpha.-m-tolylcyclohexanemethanol; 
.alpha.-(p-bromophenyl)-.alpha.-[3-(dimethylamino)propyl]cyclohexanemethano 
l; 
.alpha.-(p-chlorophenyl)-.alpha.-[3-(dimethylamino)propyl]cyclohexanemethan 
ol; 
m-chloro-.alpha.-cyclopentyl-.alpha.-[3-(dimethylamino)propyl]benzyl 
alcohol; 
.alpha.-cyclopentyl-.alpha.-[3-(dimethylamino)propyl]benzyl alcohol; 
.alpha.-[2-(dimethylamino)ethyl]-.alpha.-(p-methoxyphenyl)cyclohexanemethan 
ol 
.alpha.-[2-(diethylamino)ethyl]-.alpha.-(p-methoxyphenyl)cyclohexanemethano 
l; 
.alpha.-(p-chlorophenyl)-.alpha.-[2-(dimethylamino)ethyl]cyclohexanemethano 
l; 
.alpha.-(p-chlorophenyl)-.alpha.-[2-(diethylamino)ethyl]cyclohexanemethanol 
; 
.alpha.-(p-bromophenyl)-.alpha.-[2-(dimethylamino)ethyl]cyclohexanemethanol 
.alpha.-(p-bromophenyl)-.alpha.-[2-(diethylamino)ethyl]cyclohexanemethanol 
.alpha.-[2-(diethylamino)ethyl]-o-phenylcyclohexanemethanol 
.alpha.-(3-dimethylaminopropyl)-.alpha.-phenylcyclohexanemethanol 
.alpha.-(2-dimethylaminoethyl)-.alpha.-phenyl-1-cyclohexene-1-methanol; 
.alpha.-[5-[(2-diethylaminoethyl)methylaminolpentyl]-.alpha.-phenylcyclohex 
anemethanol; 
.alpha.-[2-(dimethylamino)ethyl]-.alpha.-(p-propoxyphenyl)cyclohexanemethan 
ol; 
.alpha.-[2-(dimethylamino)ethyl]-.alpha.-(p-methoxyphenyl)cyclohexanemethan 
ol; 
.alpha.-[2-(dimethylamino)ethyl]-.alpha.-(p-ethoxyphenyl)cyclohexanemethano 
l; 
.alpha.8 
2-(dimethylamino)ethyl]-.alpha.-(p-isopropoxyphenyl)cyclohexanemethanol; 
.alpha.-(p-butoxyphenyl)-.alpha.-[2-(dimethylamino)ethyl]cyclohexanemethano 
l; 
.alpha.-[2-(dimethylamino)ethyl]-.alpha.-(p-isobutoxyphenyl)cyclohexanemeth 
anol; 
.alpha.-[2-(dimethylamino)ethyl]-.alpha.-(p-isopentyloxy)phenylcyclohexanem 
ethanol; 
.alpha.-[2-(dimethylamino)ethyl]-.alpha.-(p-pentyloxy)phenyl]cyclohexanemet 
hanol; 
.alpha.-(4-amino-3-bromophenyl)-.alpha.-[3-diethylamino)propyl]cyclohexanem 
ethanol; 
.alpha.-(4-amino-3-chlorophenyl)-.alpha.-[3-diethylamino)propyl]cyclohexane 
methanol; 
.alpha.-(4-amino-3,5-dichlorophenyl)-.alpha.-[3-dimethylamino)propyl]cycloh 
exanemethanol; 
.alpha.-(4-amino-3,5-dichlorophenyl)-.alpha.-[3-diethylamino)propyl]cyclohe 
xanemethanol; 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-[3-dimethylamino)propyl]cyclohe 
xanemethanol; 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-[3-(ethylmethylamino)propylcycl 
ohexanemethanol; 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-[3-(diethylamino)propyl]-cycloh 
exanemethanol; 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-[3-(dipropylamino)propylcyclohe 
xanemethanol; 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-[3-(diallylamino)propylcyclohex 
anemethanol; 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-[3-(dibutylamino)propylcyclohex 
anemethanol; 
.alpha.-['4-amino-3,5-dibromophenyl)-.alpha.-[3-(cyclohexylmethylamino)prop 
yl]cyclohexanemethanol; 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-[3-(benzylmethylamino)propyl]cy 
clohexanemethanol; 
.alpha.-(4-amino-3,5-dibromophenyl)-.alpha.-[3-(N-methylanilino)propyl]cycl 
ohexanemethanol; 
N-[2,6-dichloro-4-[1-cyclohexyl-4-(diethylamino)-1-hydroxybutyl]phenyl]acet 
amide; 
.alpha.-cyclopropyl-.alpha.-[2-(dimethylamino)ethyl]benzenemethanol; 
.alpha.-cyclopropyl-.alpha.-[3-(dimethylamino)propyl]benzenemethanol; 
.alpha.-cyclopropyl-.alpha.-[2-(dimethylamino)ethyl]-4-methoxybenzenemethan 
ol 
.alpha.-cyclopropyl-.alpha.-(2-(dimethylamino)ethyl]-3-(trifluoromethyl)ben 
zenemethanol 
.alpha.-cyclopropyl-.alpha.-[2-(dimethylamino)ethyl]benzenemethanol; 
.alpha.-cyclopropyl-.alpha.-[3-(dimethylamino)propyl]benzenemethanol; 
.alpha.-cyclopropyl-.alpha.-[2-(dimethylamino)ethyl]-4-methoxybenzenemethan 
ol; 
.alpha.-cyclopropyl-.alpha.-[2-(dimethylamino)ehtyl]-3-(trifluoromethyl)-be 
nzenemethanol; 
N-[3-cyclopropyl-3-hydroxy-3-[3-(trifluoromethyl)phenyl]propyl-N-methylacet 
amide; 
3-chloro-.alpha.-cyclopropyl-.alpha.-[2-(dimethylamino)ethyl]benzenemethano 
l 
.alpha.-cyclopropyl-.alpha.-[2-(dimethylamino)ethyl]-4-(trifluoromethyl)ben 
zenemethanol 
.alpha.-cyclopropyl-.alpha.-[2-(diethylamino)ethyl]-3-(trifluoromethyl)benz 
enemethanol 
.alpha.(dimethylamino)methyl]-.alpha.-(2-methylcyclopropyl)benzenemethanol; 
.alpha.-cyclopropyl-.alpha.-2-(dimethylamino)ethyl]-4-(trifluoromethyl)benz 
enemethanol; 
.alpha.-cyclopropyl-.alpha.-[2-(diethylamino)ethyl]-3-(trifluoromethyl)benz 
enemethanol; 
3-chloro-.alpha.-cyclopropyl-.alpha.-[2-(dimethylamino)ethyl]benzenemethano 
l; 
.alpha.-(2-diethylaminoethyl)-.alpha.-phenyl-5-norbornene-2-methanol; 
.alpha.-(2-diethylaminoethyl)-.alpha.-phenyl-1-cyclohexene-1-methanol; 
.alpha.-(3-dimethylaminopropyl)-.alpha.-phenyl-cyclohexanemethanol. 
Any compound listed above may be tested by a routine screening process, as 
described in the Examples, to assess the effectiveness of that particular 
compound against cholinergic toxins used as laboratory models to simulate 
epilepsy. 
The term "hydrido" denotes a single hydrogen atom (H) which may be 
attached, for example, to a carbon atom or to an oxygen atom to form an 
hydroxyl group. The term "alkyl" embraces linear or branched radicals 
having one to about ten carbon atoms. The term "cycloalkyl" embraces 
radicals having three to about ten carbon atoms, such as cyclopropyl and 
cyclobutyl. The term "haloalkyl" embraces radicals wherein one or more of 
the alkyl carbon atoms is substituted with one or more halo groups, 
preferably selected from bromo, chloro and fluoro. Dihaloalkyl and 
polyhaloalkyl groups may be substituted with two or more of the same halo 
groups, or may have a combination of different halo groups. The terms 
"alkylol" and "hydroxylalkyl" embrace linear or branched alkyl groups 
having one to ten carbon atoms, any one of which may be substituted with 
one or more hydroxyl groups. The term "alkenyl" embraces linear or 
branched radicals having two to about ten carbon atoms and containing at 
least one carbon-carbon double bond. The terms "alkoxy" and "alkoxyalkyl" 
embrace linear or branched oxy-containing radicals having alkyl portions 
of one to ten carbon atoms, such as methoxy group. The "alkoxy" or 
"alkoxyalkyl" radicals may be further substituted with one or more halo 
atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or 
haloalkoxyalkyl groups. Examples of other substituents forming compounds 
of Formula I are as follows: 
______________________________________ 
Substituent Name Structure 
______________________________________ 
alkylcycloalkyl 
##STR8## 
acylcycloalkyl 
##STR9## 
halocycloalkyl 
##STR10## 
hydroxycycloalkyl 
##STR11## 
haloalkylcycloalkyl 
##STR12## 
aminoalkylcycloalkyl 
##STR13## 
bicycloalkyl 
##STR14## 
bicycloalkenyl 
##STR15## 
tricycloalkyl 
##STR16## 
______________________________________ 
Alkenyl and alkynyl groups may have one unsaturated bond, such as an allyl 
group, or a plurality of unsaturated bonds, with such bonds adjacent, such 
as allene-type structures, in conjugation, or separated by several 
saturated carbons. 
Included within the family of compounds of Formula I, are the tautomeric 
forms of the described compounds, isomeric forms including diastereomers, 
and the pharmaceutically-acceptable salts thereof. 
The term "pharmaceutically-acceptable salts" embraces salts commonly used 
to form alkali metal salts and to form addition salts of free acids or 
free bases. Since the compounds of Formula I contain basio nitrogen atoms, 
such salts are typically acid addition salts. The nature of the salt is 
not critical, provided that it is pharmaceutically acceptable, and acids 
which may be employed to form such salts are well known to those skilled 
in this art. Examples of acids which may be employed to form 
pharmaceutically acceptable acid addition salts include such inorganic 
acids as hydrochloric acid, sulphuric acid and phosphoric acid, and 
organic acids such as maleic acid, succinic acid and citric acid. Other 
salts include salts with alkali metals or alkaline earth metals, such as 
sodium, potassium, calcium and magnesium. All of these salts may be 
prepared by conventional means from the corresponding compound of Formula 
I by reacting, for example, the appropriate acid with the compound of 
Formula I. 
Methods of synthesis of representative compounds of Formula I are known. 
For example, synthesis of procyclidine and its salts are shown in U.S. 
Pat. No. 2,891,890 and U.S. Pat. No, 2,826,590. Synthesis of 
trihexyphenidyl hydrochloride is described in U.S. Pat. No. 2,682,543. 
Synthesis of biperiden is described in U.S. Pat. No. 2,789,110. 
Administration of compounds within Formula I to humans can be by any 
technique capable of introducing the compounds into the bloodstream of a 
human patient, including oral administration, and by intravenous, 
intramuscular and subcutaneous injections. The active compound is usually 
administered in a pharmaceutically-acceptable formulation, although in 
some acute-care situations a compound of Formula I may be administered 
alone. Such formulations may comprise the active compound together with 
one or more pharmaceutically-acceptable carriers or diluents. Other 
therapeutic agents may also be present in the formulation. A 
pharmaceutically-acceptable carrier or diluent provides an appropriate 
vehicle for delivery of the active compound without introducing 
undesirable side effects. Delivery of the active compound in such 
formulations may be by various routes including oral, nasal, topical, 
buccal and sublingual, or by parenteral administration such as 
subcutaneous, intramuscular, intravenous and intradermal routes. 
EXAMPLES 
Example 1: 
Pilocaroine assay using procyclidine as pre-treatment 
Adult male Sprague Dawley rats (300-400 g) were treated with lithium 
chloride (3 meq/kg subcutaneous (sc)), to potentiate the pilocarpine 
effect and reduce individual variability among the rats. One day later the 
experimental group was treated with procyclidine (75 mg/kg intraperitoneal 
(ip)). The control group was treated with an equivalent volume of saline. 
Thirty minutes later, both groups received a single treatment with 
pilocarpine (30 mg/kg sc). 
Rats were observed over a 4 hour period for behavioral signs of 
neurotoxicity, including preconvulsive signs such as facial grimacing, 
head nodding, eye blinking, wet dog shakes, or evidence of convulsions, 
including rearing on hind limbs with clonic movements of the head and 
forelimbs. After 4 hours, they were anesthetized and perfused through the 
left cardiac ventricle and ascending aorta with an aldehyde fixative 
solution for 15 minutes, then the brains were removed from the skull and 
processed for histopathological evaluation by methods previously described 
for light and electron microscopy (Olney 1971). 
The results were as follows: all of the rats in the saline control group, 
i.e., rats that received lithium/pilocarpine but not procyclidine, 
displayed the full behavioral syndrome of preconvulsive and convulsive 
symptoms with persistent seizure activity being present for the majority 
of the 4 hour observation period. All of these rats in the saline control 
group (n=6) had severe brain damage affecting the cerebral cortex, 
hippocampus, amygdala, piriform cortex, thalamus, lateral septum and 
substantia nigra. None of the treated rats (lithium/pilocarpine and 
procyclidine) displayed either preconvulsive or convulsive signs, and none 
(n=6) sustained brain damage. 
EXAMPLE 2 
Pilocarpine assay using procyclidine as post-treatment 
In a second experiment, all conditions were the same except that the 
procyclidine (75 mg/kg i.p.) or saline was not administered until 30 min 
after pilocarpine. All of the rats in the saline control group (n=6) 
exhibited a full behavioral syndrome, including persistent seizures and 
disseminated brain damage. 
Most of the rats in the treatment group had begun to seize before 
procyclidine was administered, but all convulsive behavior disappeared 
within 10 minutes after procyclidine administration and all of these rats 
(n=6) escaped brain damage. 
Prior research on receptor binding data had suggested that procyclidine 
interacts weakly with phencyclidine receptors (Olney et al 1987). In 
addition, recent research by the inventor of the subject application 
(Olney 1989) indicated that phencyclidine and MK-801 can cause vacuolar 
cytopathological changes in the posterior cingulate and retrosplenial 
cerebral cortices. The correlation of those findings suggests that 
procyclidine might also cause some degree of PCP-like toxicity. To 
evaluate that possibility, the affected brain regions were examined in the 
rats (n=12) from the treatment groups in both of the the experiments 
described above (i.e., rats that received procyclidine either before or 
after the pilocarpine). There was no evidence of the vacuolar 
cytopathology that occurs following phencyclidine or MK-801 treatment. 
EXAMPLE 3 
Soman assay using procyclidine as post-treatment 
A major problem in studying the soman cholinotoxic syndrome is the marked 
individual variation in sensitivity of experimental animals. Some adult 
rats develop status epilepticus (persistent seizures) within 5-15 minutes 
after receiving a dose of soman in the range of 90-125 ug/kg 
(micrograms/kilogram) i.p. Those animals typically sustain severe brain 
damage and die within 1 to hours. However, other rats can tolerate much 
higher doses of soman without exhibiting seizures or brain damage and such 
animals survive treatment without any apparent untoward effects. 
Administering lithium chloride 24 hours prior to soman causes a moderate, 
but consistent, increase in the percentage of animals susceptible to soman 
neurotoxicity. 
In a study to evaluate the possibility that procyclidine might protect 
against the neurotoxic effects of soman, adult male Sprague Dawley rats 
(350-425 g) were pretreated with lithium chloride (3 mg/kg sc) and 24 hrs 
later given soman (125 ug/kg sc) and observed for symptoms. Animals that 
began convulsing were treated immediately either with saline (control 
group) or a single dose (75 mg/kg i.p.) of procyclidine (treatment group). 
Animals that did not convulse received no further treatment. 
All animals were anesthetized and killed 4 hours after soman treatment and 
their brains examined histologically by methods described above. Rats that 
did not seize (n=28) did not have any brain pathology. All rats that 
seized and received saline (n=8) had severe disseminated brain damage. 
Rats that seized and received procyclidine (n=2), stopped seizing within 5 
to 15 minutes; all of these rats escaped brain damage. 
In a separate experiment, atropine, which like procyclidine is classified 
as an anti-cholinergic drug, was substituted for procyclidine in the above 
protocol. At doses up to 100 mg/kg i.p., atropine conferred no protection 
against soman neurotoxicity. 
EXAMPLE 4 
Soman assay using selected susceptible rats 
In an additional experiment, the neuroprotective properties of procyclidine 
were exploited to establish a colony of rats selectively bred for 
increased susceptibility to soman neurotoxicity. Adult male and female 
rats were challenged with soman. Those that responded with seizures (n=8) 
were identified as soman-sensitive and were treated with procyclidine 
which protected them, allowing them to survive and serve as breeding 
stock. 
The first generation offspring of soman-sensitive male/female matings were 
challenged with soman and found to have a substantially increased rate of 
soman sensitivity (increased from 40% to 80%), even though lithium 
pretreatment was not used. Administration of procyclidine to these animals 
(n=8) when they started seizing, consistently caused cessation of seizures 
and protection against brain damage. 
Thus, if experimental animals from the above studies are combined, the 
total number of rats protected against soman neurotoxicity by 
administration of procyclidine following onset of convulsive symptoms is 
28. Although lithium pretreatment was employed in the first experiment, 
rats in the latter two experiments (n=16) received soman without lithium 
pretreatment. Therefore, either in the presence or absence of lithium, 
procyclidine provides effective protection against soman neurotoxocity. 
EXAMPLE 5 
Treatment with Biperiden or Trihexyohenidyl 
Preliminary tests using a small number of rats were performed to determine 
whether biperiden or trihexyphenidyl were effective against a cholinergic 
neurotoxin. Rats were subjected to lithium priming and pilocarpine 
exposure as described in Example 2, and rats that showed seizure activity 
were treated with either biperiden or trihexyphenidyl. In all such rats, 
seizure activity ceased, and histological examination did not indicate any 
brain damage. 
The positive results described above indicate that these compounds will be 
at least partially effective against temporal lobe epilepsy, and possibly 
against other forms of epilepsy as well. 
Although this invention has been described with respect to specific 
embodiments, the details of these embodiments are not to be construed as 
limitations. Various equivalents and modifications may be made without 
departing from the spirit and scope of this invention, which is limited 
only by the claims which follow. 
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