Structure-Activity Relationships (SAR) of PCP analogs:

> Only a few PCP derivatives have been formally tested for activity in man, but there is a large amount of data available comparing the potency of various compounds in animals. A number of different assays have been used to evaluate the activity of PCP derivatives. Binding data at the noncompetitive NMDA receptor at which PCP binds and produces its characteristic effects (the "PCP receptor"), provides much of the potency data for the various compounds. However, it should be noted that this assay only measures the affinity of a compound for the receptor, and does not reveal whether a compound might have agonist or antagonist activity. Thus a compound that shows high affinity for the PCP receptor may not necessarily produce effects in animals similar to PCP.

> Data on the potency of PCP derivatives can also be derived from various in vivo pharmacological tests.Two of the most important are the rat rotorod and pigeon catalepsy tests, in which an animal is administered a test compound and its behavior observed. The most reliable data is obtained when both receptor binding assays and in vivo evaluation are compared. For the most part, receptor binding assays and in vivo evaluations agree closely as to whether a particular compound shows a PCP-like profile. However, there are some important exceptions (e.g. ref. 25, 26).

> It should be noted that the data presented here should not be used as an exact guide to potency, but rather as a rough comparison. Depending on the particular assay used, there may be a discrepency in the rank order of potency among the analogs, but generally the various tests are all able to predict whether a given compound is active at all.

> Also note that there are some subtle differences among the compound's behavioural effects in animals. For instance, the potent analogs TCP and PCPy (thienyl cyclohexylpiperidine and phenyl cyclohexylpyrrolidine) have been shown to increase ambulation in mice as well as producing a sedating "taming" effect (ref 11). PCE shows a similar, but smaller, increase in ambulation. This is in contrast to PCP, which causes a decrease in ambulation. This effect can be interpreted as an increased stimulant component of their action, and there is some anecdotal evidence that TCP has a more stimulant profile in man than PCP, although the effect is probably rather subtle (ref 14).

> The majority of analogs tested have reduced potency compared to PCP. For instance ketamine is only 1/10 as active as PCP. However, considering the potency of PCP, this is still respectable, giving an approximate dosage in man of 100 mg.

Structural modification of PCP. Three possibilities: (ref. 1, 10-11)

> 1) Replacement of the piperidine ring by other amines.

> 2) Adddition of substituents to the phenyl ring, or replacement by other aromatic rings.

> 3) Modification of the cyclohexyl ring.

1. Modification of the amine substituent:

> A. noncyclic alkyl substituents: Replacement of the piperidine ring in PCP by other alkyl groups can lead to many active compounds. Removal of all N-alkyl substituents gives a compound about 1/2 as potent as PCP (1-phenylcyclohexylamine, PCA). Small alkyl substituents such as methyl and ethyl give compounds with increased potency relative to PCA. An N-methyl group gives a compound with about the same order of potency as PCP (possibly slightly lower). Lengthening the alkyl chain from methyl to ethyl increases the potency, and PCE is more active than PCP.

> Further increasing the chain length to n-propyl or n-butyl leads to a decrease in potency, although the n-propyl compound is still of similar potency to PCP.

> There is some evidence that smaller mono N-alkyl substituents such as methyl or ethyl lead to compounds with increased tendency to produce nausea. Additionally, the freebase of these analogs has a very unpleasant caustic taste when vaporized and inhaled, in contrast to the reportedly pleasant menthol flavor of PCP base. Formation of the HCl salts increases the palatability somewhat, although with PCE, there is still a distinctly unpleasant flavor (ref 14).

> The N-ethyl derivative of PCP (PCE, evaluated for anesthetic potential as CI-400 by Parke Davis Co.) began to be seen in clandestine labs in the US in 1970, following which it was legally scheduled. Another similar analog that has appeared on the illicit market in the US is the N-propyl homolog (PCPr), which has not been scheduled. The compound with an N-isopropyl substituent appears to have similar potency to PCP, but the N,N-dimethyl derivative may be only 1/2 the potency of PCP. The N,N-diethyl compound has more active in animal models than the dimethyl analog, but still less than PCP.

> An oxygen atom can be incorporated into the alkyl chain of the amino substituent to give a compound that retains activity. For instance, both the N-(2-methoxy-ethyl) and N-(3-methoxy-propyl) analogs are active in animal models (ref 11). The N-(2-hydroxy ethyl) analog has also been found on the street, and is presumably active.

> B. cyclic alkyl substituents: Replacing the six-membered piperidine ring with the five-membered pyrrolidine ring gives the compound PCPy. This compound is only slightly less potent than PCP and has appeared on the street in both the US and Europe. It is now a schedule I controlled substance in the US. One report from a DEA internal publication mentions that although PCPy shows PCP-like activity in animals, it was found on the street to produce a barbituate-like intoxication and was not accepted (ref. 13). However, recent uncontrolled experimentation in humans shows that the effects are at most only subtly different from PCP, and for the most part virtually indistinguishable (ref. 14).

> Replacement of the piperidine ring with a morpholine ring produces a compound that is 1/10 the potency of PCP. In one study this compound was shown to be somewhat more potent than ketamine in animals trained to self-inject (ref. 48).

> Alkyl substituents on a piperidine ring may also give active compounds. For instance the racemic 4-methyl and 3-methylpiperidine analogs retain about 1/3 of the activity of PCP. Increasing the size of the piperidine to a 7 membered ring (hexamethyleneimine) also gives a compound in the same order of potency as PCP. Some alkyl-substituted pyrrolidine analogs are also active, such as 3,3-dimethylpyrrolidine.

2. Modification of the aromatic (phenyl) ring:

> a. Replacement of phenyl ring: The phenyl ring of PCP can be replaced with a wide variety of other aromatic rings and maintain activity. Maintaining electron density in the ring appears to be vital to maintain activity. Substituting a 2-thienyl ring gives the compound TCP (1-thienylcyclohexylpiperidine, fig. 1), which is up to four times as potent as PCP depending on the particular assay used. Subjective effects of TCP in man are almost indistinguishable from PCP, and only somewhat stronger on a weight basis (ref. 14).

> Synthesis of TCP is easily accomplished by substitution of 2-bromothiophene for bromobenzene in the grignard reaction. TCP was entered into schedule I of the Controlled Substance Act in the US in 1975, after it began to appear widely on the street beginning in 1972. Another analog that has appeared on the street and been placed into Schedule I is TCPy, or l-[l-(2-thienyl)cyclo-hexyl]cyclohexyl]pyrrolidine, the analog of PCP resulting from replacement of the piperidine ring with pyrrolidine and the phenyl ring with thiophene. This compound appears to be approximately as potent as PCP in animal tests.

> b. Addition of substituents to the phenyl ring: Many PCP derivatives have been synthesized in which the phenyl ring carries various substituents. Only a few substituents are known that increase potency.

> > 1. Substituents at the 3-postition of the phenyl ring: A 3-methoxy group gives a compound that is capable of producing effects in man that are extremely similar to PCP in potency and quality (ref. 14). The 3-hydroxy compound however, has 8 times the affinity of PCP for its receptor but also has profoundly enhanced affinity for the opiate receptor (430 times the affinity of PCP), giving it an analgesic activity 1 order of magnitude lower than morphine. Substitution of the 3-OH group with an amino group results in other compounds with increased analgesic effects, again probably because of increased activity at an opiate receptor.

> > Electron withdrawing groups seem to have a deactivating effect. A fluoro substituent or other halogen at the 3 position strongly reduces activity, as does a 3-nitro group. Howver, a methyl group at this position gives a compound that retains activity (ref 11).

> > 2. Substituents at the 4-postition of the phenyl ring: In the 4-position, chloro, methyl, and nitro groups give inactive compounds. A 4-fluoro or 4-methoxy group results in a compound that is active but of somewhat reduced potency. A 4-hydroxy phenyl substituent appears to yield a compound that is at least as active as PCP, and possibly more so.

> > 3. Substituents at the 2-postition of the phenyl ring: Ketamine is notable for possesing a 2-chloro group. This substituent most likely decreases overall potency of the compound, but may enhance analgesic activity. A 2-methoxy group may also give an active compound (ref 11).

3. Modification of the cyclohexyl ring:

> The cyclohexyl ring appears to be the optimum size for maximum potency within PCP derivatives. Increasing or decreasing the size of the ring to cycloheptyl or cyclopentyl results in a drastic decrease in activity. However, increasing the size of the cyclohexane ring may increase the affinity of the compound at dopamine receptors, as discussed later.

> Ketamine (1-(2-chlorophenyl)-1-methylamino-(2-cyclohexanone, figure 1) has a carbonyl substituent at the two-position of the cyclohexane ring. This confers the desirable property of increasing elimination and decreasing the duration of anesthetic action, and may enhancie the analgesic potency. The veterinary anesthetic tiletamine (the N-ethyl 2-thienyl analog of Ketamine, figure 1) also has a carbonyl group at the same position.

> If the carbonyl group is moved to the 4-position of the cyclohexane ring, compounds that are active analgesics comparable to morphine can result, along with a reduction in PCP-like activity.

> Adding a 2 or especially 4-methyl substituent to the cyclohexane ring increases activity (ref 54). Adding a hydroxy group at any position decreases activity at the PCP receptor by a factor of 10 to 80.

Summary of SAR. Promising analogs:

> There are a number of PCP analogs that seem particularly promising for exploration. In trying to predict which analogs may appear as illicit drugs in the future, there are several factors to consider. 1). The compound should be predicted to be fairly potent, or there should be potency data available in the literature. 2) The compound should not be previously scheduled as a controlled substance. 3) It should be easily synthesizable, preferably with inexpensive and readily available chemicals.

> Keeping these factors in mind, the following compounds may be particularly suitable candidates for clandestine synthesis:

> Analogs with a propyl or isopropyl amino substituent replacing the piperidine ring (N-propyl-1-phenylcyclohexylamine and N-isopropyl-1-phenylcyclohexylamine), as well as their thiophene counterparts. Also the N-ethyl homolog, N-ethyl thiophenylcyclohexylamine.

> Analogs with a 3-methoxyphenyl group are also good candidates, such as the piperidine, pyrrolidine, N-ethyl, and N-propyl analogs.

> Compounds with a 2 or 4-methyl cyclohexyl substituent will also be quite potent, although the cost of the starting material (2 or 4-methyl cyclohexanone) may be more expensive.

> Next Section: Current Research on PCP Analogs

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