(+)-CPCA

Template:Chembox new The Nocaine tag can be applied to a diverse assortment of piperidine cocaine mimics.

Methylphenidate Analogs

Inhibition of [¹²⁵I]RTI-55 Binding (Ki, nM) and [³H]Monoamine Uptake (IC50, nM) by (±)-threo diastereoisomers.

Identification Marker			DAT (Ki, nM) IC50, nM			NET (Ki, nM) IC50, nM			SERT (Ki, nM) IC50, nM
R	X	N	[125I]RTI-55	[3H]Dopamine	D.R.	[125I]RTI-55	[3H]NE	D.R.	[125I]RTI-55	[3H]SERT	D.R.
MeOC=O	H	H	110 ± 9	79 ± 16	0.7182	660 ± 50	61 ± 14	0.09242	65K ± 4K	51K ± 7K	0.7846
O=COMe	p-Cl	H	25 ± 8	11 ± 2	0.44	110 ± 40	11 ± 3	0.1	6K ± 100	>9.8K	>1.633
Methyl	p-Cl	H	180 ± 70	22 ± 7	0.1222	360 ± 140	35 ± 13	0.9722	4.9K ± 500	1.9K ± 300	0.3878
Ethyl	p-Cl	H	37 ± 10	23 ± 5	0.6216	360 ± 60	210 ± 30	0.5833	7.8K ± 800	2.4K ± 400	0.3077
n-propyl	p-Cl	H	11 ± 3	7.4 ± 0.4	0.6727	200 ± 80	50 ± 15	0.25	2.7K ± 600	2.9K ± 1100	1.074
i-propyl	p-Cl	H	46 ± 16	32 ± 6	0.6957	810 ± 170	51 ± 20	0.06296	5.3K ± 1300	3.3K ± 400	0.6226
n-butyl	p-Cl	H	7.8 ± 1.1	8.2 ± 2.1	1.051	230 ± 30	26 ± 7	0.1130	4.3K ± 400	4K ± 400	0.9302
i-butyl	p-Cl	H	16 ± 4	8.6 ± 2.9	0.5375	840 ± 130	120 ± 40	0.1429	5.9K ± 900	490 ± 80	0.08305
n-pentyl	p-Cl	H	23 ± 7	45 ± 14	1.957	160± 40	49 ± 16	0.3063	2.2K ± 100	1.5K ± 300	0.6818
i-pentyl	p-Cl	H	3.6 ± 1.2	14 ± 2	3.889	830 ± 110	210 ± 40	0.2530	5K ± 470	7.3K ± 1400	0.1137
neo-pentyl	p-Cl	H	120 ± 40	60 ± 2		140 ± 400	520 ± 110
c-pentmethyl	p-Cl	H	9.4 ± 1.5	21 ± 1		1700 ± 310	310 ± 40
c-hexmethyl	p-Cl	H	130 ± 40	230 ± 70		4200 ± 200	940 ± 140
benzyl	p-Cl	H	440 ± 110	370 ± 90		2900 ± 800	2900 ± 600
phenethyl	p-Cl	H	24 ± 9	160 ± 20		1800 ± 600	680 ± 240
phenpropyl	p-Cl	H	440 ± 150	290 ± 90		490 ± 100	600 ± 140
3-pentyl	p-Cl	H	400 ± 80	240 ± 60		970 ± 290	330 ± 80
c-pentyl	p-Cl	H	36 ± 10	27 ± 8.3		380 ± 120	44 ± 18
i-butyl	m-Cl	H	3.7 ± 1.1	2.8 ± 0.4		23 ± 6	14 ± 1

Recently, some new methylphenidate analogs have been prepared by Froimowitz et al.^[1] In stark contrast to Nocaine, the RR isomer serves as the eutomer. An almost perfect computational overlap with the PT's was ample motivational driving force for conducting these studies.

Nocaine Pharmacology

Some JPET studies have been conducted on SS and (3R,4S) Nocaine, respectively.^[2][3] Factors such as reinforcing ability and seizure thresholds were explored.

"The present study investigated the pharmacological properties of a piperidine-based novel cocaine analog, namely, (+)-methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid [(+)-CPCA]. Like cocaine, (+)-CPCA inhibited rat synaptosomal dopamine and norepinephrine uptake with high affinity, but was 33-fold less potent than cocaine in inhibiting serotonin uptake. Like cocaine, (+)-CPCA is a locomotor stimulant, although it was less potent and efficacious than cocaine. Importantly, pretreatment with (+)-CPCA dose dependently blocked the locomotor stimulant effects of cocaine in rats. (+)-CPCA completely substituted for cocaine in drug discrimination tests, although it was about 3 times less potent than cocaine. It was also self-administered by rats. Unexpectedly, (+)-CPCA did not enhance cocaine-induced convulsions in mice. As expected from rodent studies, rhesus monkeys readily self-administered (+)-CPCA. However, compared with cocaine, (+)-CPCA showed limited reinforcing properties in rats as assessed by both fixed and progressive ratio intravenous drug self-administration tests. These results collectively suggest that (+)-CPCA has an atypical pharmacological profile having both cocaine-like "agonist" and some cocaine "antagonist" properties. These properties of (+)-CPCA suggest that it may have utility in the treatment of cocaine craving and dependence."

"Drugs that block dopamine uptake often function as positive reinforcers but can differ along the dimension of strength or effectiveness as a positive reinforcer. The present study was designed to examine pharmacological mechanisms that might contribute to differences in reinforcing strength between the piperidine-based cocaine analog (+)-methyl 4-(4-chlorophenyl)-1-methylpiperidine-3--carboxylate [(+)-CPCA] and cocaine. Drugs were made available to rhesus monkeys (n = 5) for i.v. self-administration under a progressive ratio schedule. Both compounds maintained responding with sigmoidal or biphasic dose-response functions (0.1-1.0 mg/kg/injection). (+)-CPCA was one-fourth as potent as cocaine and maintained fewer injections per session, at maximum. For in vitro binding in monkey brain tissue, (+)-CPCA was about one-half as potent as cocaine at the dopamine transporter (DAT), and the two compounds had similar affinities at the norepinephrine transporter. (+)-CPCA was less than 1/10 as potent as cocaine at the serotonin transporter. In ex vivo binding in rat striatum, occupancy of the DAT increased directly with dose to a maximum of approximately 80% for both compounds, and (+)-CPCA was about one-fourth as potent as cocaine. Ex vivo DAT occupancy was significantly higher for cocaine than (+)-CPCA at 2 min after injection but similar at other times. Thus, the primary differences between these compounds were in serotonin transporter affinity and the kinetics of DAT binding. These results suggest that (+)-CPCA is a weaker positive reinforcer than cocaine because it has a slower onset of action over the first few minutes after i.v. injection."

The vinyl compound was picked to represent this series of compounds in LMA studies. Both cocaine and the vinyl compound stimulated LMA. However, cocaine is ~2.5 x more potent in increasing the distance traveled. In contrast, the vinyl compound is about ~2.4 x more potent in enhancing stereotypic movements. Both cocaine and vinyl-Nocaine had a similar time-course on locomotor effects, which was ~2 h.

First Nocaine Triple Monoamine QSAR^[4]

Based upon the results reported in the tropane series, it became desirable to manipulate the weak phenyl-arecoline nucleus in ways that that would improve SERT affinity, and also strengthen DAT binding. A series of Nocaine analogs were tested at the three common monoamine transporters for their ability to inhibit the reuptake of radiolabelled tritium neurotransmitters, respectively. The uptake data and selectivity profiles of these compounds are listed in the table.

First Nocaine Triple Monoamine QSAR

Identification Marker			SERT / DAT / NET IC50, nM (Ki, nM)			IC50 ÷ Ki			Uptake Ratio
Config	X	N	[3H]Serotonin	[3H]Dopamine	[3H]Noradrenaline	SER	DA	NE	DA/5HT	NA/SER	NE/DA
SS	p-Vinyl	Me	155 ± 3.9 (138 ± 3.5)	144 ± 20 (131 ± 18)	204 ± 5.6 (175 ± 4.8)	1.123	1.099	1.166	0.9493	1.268	1.336
SS	p-Ethyl	Me	275 ± 39 (255 ± 37)	>1800 (>1700)	>1300 (>1100)	1.078	1.059	1.182	>6.667	>4.314	0.6471
SS	p-Allyl	Me	334 ± 48 (309 ± 44)	>1000 (964 ± 100)	>1200 (>1000)	1.081	>1.037	1.2	3.120	>3.236	1.037
SS	p-Ethynyl	Me	189 ± 37 (175 ± 34)	213 ± 30 (187 ± 26)	399 ± 12 (364 ± 9.2)	1.080	1.139	1.096	1.069	2.080	1.947
SS	p-Phenyl	Me	67 ± 4.5 (62 ± 4.1)	184 ± 30 (173 ± 26)	239 ± 42 (203 ± 36)	1.081	1.064	1.177	2.790	3.274	1.173
SS	2-Naphthyl	Me	8.2 ± 0.3 (7.6 ± 0.2)	23 ± 1.0 (21 ± 0.9)	n.d. (34 ± 0.8)	1.079	1.095		2.763	4.474	1.619
(3R,4S)	2-Naphthyl	Me	46 ± 4.4 (42 ± 4.0)	>1000 (947 ± 135)	n.d. (241 ± 1.7)	1.095	>1.056		22.55	5.738	0.2545
RR	2-Naphthyl	Me	209 ± 17 (192 ± 16)	94 ± 9.6 (87 ± 8.9)	n.d. (27 ± 1.6)	1.089	1.080		0.4531	0.1406	0.3103
(3S,4R)	2-Naphthyl	Me	13 ± 0.7 (12 ± 0.7)	293 ± 6.4 (271 ± 5.9)	n.d. (38 ± 4.0)	1.083	1.081		22.58	3.167	0.140
(3S,4R)	2-Naphthyl	H2Cl	3.9 ± 0.5 (3.5 ± 0.5)	97 ± 8.6 (90 ± 8.0)	34 ± 2.5 (30 ± 2.3)	1.114	1.078	1.133	25.71	8.571	0.3333
β±	1-Naphthyl	Me	113 ± 4.3 (101 ± 3.8)	326 ± 1.2 (304 ± 1.1)	337 ± 37 (281 ± 30)	1.119	1.072	1.199	3.010	2.782	0.9243
All data are mean values ± range or SEM of 2–5 separate experiments each conducted with 6 drug concentrations in triplicate.

http://www.unmc.edu/Pharmacology/receptortutorial/competition/analysis_sample4.htm

Human Embryonic Kidney (HEK)

"A series of 3-carbomethoxy-4-(aryl-substituted)piperidines with various aryl groups were synthesized and examined for binding and reuptake inhibition at the human dopamine transporter, the human serotonin transporter, and the human norepinephrine transporter. The binding potency and reuptake inhibition efficacy was compared with that of (−)-cocaine to determine the significance of removing the two-carbon bridge of the cocaine nucleus on the inhibition of transporter binding and reuptake. Of the transporters examined, the substituted piperidines were relatively selective for the human dopamine transporter. In all cases examined, the cis-diastereomer of the 3-carbomethoxy-4-(aryl-substituted)piperidine was observed to be a more potent inhibitor of the human dopamine transporter than the trans diastereomer. Based on the Ki (binding) and IC50 (reuptake inhibition) values obtained, the most potent inhibitor of the series was cis-3-carbomethoxy-4-(4′-chlorophenyl)piperidine, and this compound suppressed spontaneous- and cocaine-induced stimulation in non-habituated male Swiss-Webster mice. The conclusion is that substantial portions of the cocaine structure can be dissected away to provide compounds with significant binding and reuptake inhibition of the human dopamine transporter."^[5]

Human Embryonic Kidney cells: Nocaine

Tag			hDAT / hSERT / hNET IC50, nM (Ki, nM)			D.R. IC50 ÷ Ki
Con.	X	Y	HEK hDAT	HEK hSERT	HEK hNET	hDAT	hSERT	hNET
β±	Cl	H	151 ± 6.88 (98.9 ± 6.42)	544 ± 208 (684 ± 205)	1841 ± 421 (2201 ± 545)	1.53	0.79	0.84
β±	Me	H	340 ± 55.9 (340 ± 26.1)	793 ± 75 (2248 ± 330.7)	724 ± 243 (2441 ± 141)	1.0	0.35	0.296
β±	H	H	4657 ± 2171 (5135±1463)	2198 ± 758 (>10uM)	1282 ± 262 (>10uM)	0.91	0.22	0.13
β±	F	H	1789 ± 581 (2665 ± 605)	3414 ± 591 (10uM)	4852 ± 1852 (10uM)	0.67	0.34	0.48
α±	Cl	H	325.2 ± 63.9 (356 ± 18.0)	3133 ± 67 (5223 ± 2127)	2084 ± 75 (2279 ± 843)	0.9	0.6	0.91
α±	Me	H	446.2 ± 126 (2038 ± 561)	2868 ± 931 (>10uM)	1127 ± 387 (>10uM)	0.22	0.29	0.11
α±	H	H	>10uM (>10uM)	3891 ± 160 (>10uM)	2706 ± 894 (>10uM)	1.0	0.39	0.27
αβ±	OMe	H	4737 ± 2049 (4615 ± 894)	687 ± 57 (1287 ± 335.1)	>10uM (>10uM)	1.03	0.83	1
αβ±	H	OMe	>10uM (>10uM)	438 ± 225 (2518 ± 689)	>10uM (>10uM)	1.0	0.17	1
αβ±	F	H	988 ± 465 (6831 ± 743.5)	3025 ± 313 (>10uM)	>10uM (>10uM)	0.14	0.3	1

"When the IC₅₀ value for neurotransporter reuptake inhibition is divided by the binding constant for inhibition of radiolabelled RTI-55 binding to provide a ratio this correlation ratio value can provide insight into the efficacy of a compound as an antagonist of cocaine action. An IC₅₀/Ki correlation ratio of 25 or greater suggests that the compound possesses binding potency and reuptake inhibition efficacy of sufficient magnitude to compete with the pharmacological effects exerted by cocaine. However, none of the compounds examined attained the desired level of activity."

Nocaine: Ester and Amine Modifications

A series of novel N- and 3α-modified Nocaine analogs were synthesized and tested for their SNDRI activity.^[6] N-Demethylation of (+)-3α-piperidine-based ligands gave improved SER/NET activity and modestly weaker DAT binding. In vivo metabolism of Nocaine is likely to involve some N-demethylation. Far more fundamental will be the in vivo conversion of the –CO2Me to –CO2H. Whether this occurs by esterase action or is just a straightforward hydrolysis is immaterial, but the net-result is a MAT dummy.

The Nor-Nocaines show increased SERT/NET affinity but in some cases DAT binding may be marred. This is a rather dramatic effect and should not be taken lightly.

The in vitro demethylation results displayed in the table are in solid agreement with PT compounds.

Nocaine: N-demethylation and Ester Reduction QSAR

Configuration	R	N	[3H]DA Ki(nM)	[3H]SER Ki(nM)	[3H]NE Ki(nM)
(3R,4S)	MeOCO	Me	233 ± 62	8490 ± 1430	252 ± 43
(3R,4S)	HOCH2	Me	497 ± 58	1550 ± 360	198 ± 53
(3R,4S)	MeOCO	H	279 ± 98	434 ± 50	7.9 ± 3.0
(3R,4S)	HOCH2	H	836 ± 35	239 ± 28	69 ± 6

Nocaine-CH₂OH is a very respectable 2 x weaker than Nocaine at the DA transporter. Moreover, Nocaine-CH₂OH possesses 5.5 х stronger SERT affinity than Nocaine, whereas NET binding remains more or less constant.

LMA tests in mice and drug discrimination tests in rats were conducted. The behavioral effects of Nocaine was studied earlier, where it was shown to be a good stereo-enhancer but inferior to the PT's with regards to LMA. The lack of convulsion potential of Nocaine is valuable observation that should be reiterated.

Modafinil Hybrids

A range of bivalent α-(4-chlorophenyl) arecoline compounds were prepared in enantiomerically pure form. The optimum chain length of the spacer for SERT activity was five carbons long. In the case of the (3S,4R) enantiomer this led to the creation of an SSRI that was approaching <1nM activity. A suitable explanation for this might be that the separation distance between the two molecules is just right to allow binding onto two adjacent receptors. The chain length and choice of enantiomer were altered to yield other active inhibitors with varying potencies and SERT/NET/DAT ratios.

In another study a large number of derivatives of Nocaine were prepared that contain a highly functionalized thioalkyl chain at the 3 position. Most of these ligands were more potent inhibitors at NET compared to DAT or SERT. However, in the case of the ligand depicted, activity at all three MA systems was bordering on <1nM affinity.

File:Kozikowski 16e.png

The side-chain of the wake-promoting agent modafinil was used as a punitive lead to fuel this compounds discovery.^{[7] [8] [9] [10][11]}

Meperidine Analogs

In Vitro Data for Meperidine Analogs with Tritiated Radiotracers.

Tag		DAT / SERT / Opioid (Ki, μM) and Dopamine (IC50, μM)				Uptake Ratio
E	Ar	[3H]WIN 35,428	[3H]Paroxetine	[3H]DAMGO	[3H]Dopamine	DAT/SERT	μ/DAT	μ/SERT
CO2Et	Ph	17.8 ± 2.7	0.413 ± 0.044	0.92	12.6 ± 1.2	43.1	0.052	2.13
CN	p-F	45†	10.1 ± 0.4	15†	8†	nd	nd	nd
CN	p-Cl	22.0 ± 10.1	5.11 ± 0.59	36.8 (51)†	36†	4.31	1.67	0.18
CN	p-I	8.34 ± 0.67	0.430 ± 0.0034	17.3 (61)†	36.7 ± 1.3	19.4	2.07	40.2
CN	p-Me	41.8 ± 6.1	13.7 ± 0.4	40.6 (46)†	22†	3.05	0.97	2.96
CN	m,p-Cl2	2.67 ± 0.24	0.805 ± 0.12	40.0 (46)†	11.1 ± 1.2	3.32	15.0	49.7
CN	β-Naph	2.36 ± 0.66	0.125 ± 0.022	15.4 (61)†	21.8 ± 1.2	18.9	6.53	123
CO2Et	p-F	10.7 ± 2.3	0.308 ± 0.026	1.47	47†	34.7	0.14	4.77
CO2Et	p-Cl	4.10 ± 1.27	0.277 ± 0.040	4.41	26.9 ± 1.2	14.8	1.08	15.9
CO2Et	p-I	3.25 ± 0.20	0.0211 ± 0.0024	2.35	11.1 ± 1.2	155	0.72	111
CO2Et	p-Me	12.4 ± 5.2	1.61 ± 0.11	2.67	76.2 ± 1.2	7.69	0.22	1.66
CO2Et	m,p-Cl2	0.125 ± 0.015	0.0187 ± 0.0026	2.04	1.40 ± 1.25	6.68	16.3	109
CO2Et	β-Naph	1.14 ± 0.38	0.0072 ± 0.0001	2.03	11.6 ± 1.3	158	1.78	282
All values are the mean ± SEM of three experiments performed in triplicate. † Percent inhibition at highest dose tested (100μM).

Some analogs of meperidine were prepared, initially with a bias toward improving DAT binding, but it turned out that these analogs favor the SERT and can even be made selective for this transporter under optimum circumstances.^[12][13] The authors seemed unable to accept this though, and instead chose to modify the -CO₂Et to try and improve DAT binding.^[14] None of the analogs tested produced LMA effects or substituted for cocaine in drug discrimination studies. The authors hypothesized that opioid receptor involvement is accountable for the lack of LMA of these analogs.

External links

Patents

Clarke Patent^[15] Kozikowski Patents^{[16][17][18][19][20][21]}

Neurosearch

The present invention relates to novel piperidine-derivatives which are valuable monoamine neurotransmitter, i.e dopamine, serotonin and noradrenaline, re-uptake inhibitors and the use of the novel piperidine derivatives for the treatment of disorders or diseases responsive to the inhibition of monoamine neurotransmitter re-uptake, including diseases such as Parkinson's disease, depression, obsessive compulsive disorders, panic disorders, dementia, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety, eating disorders and drug addiction or misuse, including cocaine abuse.^[22]

This invention relates to novel piperidine derivatives useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.^[23]

References

1. [1]Froimowitz, M.; Gu, Y.; Dakin, L. A.; Nagafuji, P. M.; Kelley, C. J.; Parrish, D.; Deschamps, J. R.; Janowsky, A. J. Med. Chem.; (Article); 2007; 50(2); 219-232.
2. [2]J. Pharmacol. Exp. Ther. 2003 305: 143-150. Nocaine
3. [3]J. Pharmacol. Exp. Ther. 2002 303: 211-217.
4. [4]Amir P. Tamiz, Jianrong Zhang, Judith L. Flippen-Anderson, Mei Zhang, Kenneth M. Johnson, Olivier Deschaux, Srihari Tella, and Alan P. Kozikowski. J. Med. Chem.; 2000; 43(6) pp 1215 - 1222
5. [5]X. Feng et al. Bioorganic & Medicinal Chemistry Volume 11, Issue 5 , 6 March 2003, Pages 775-780
6. [6]Pavel A. Petukhov, Jianrong Zhang, Alan P. Kozikowski, Cheng Z. Wang, Yan Ping Ye, Kenneth M. Johnson, and Srihari R. Tella J. Med. Chem.; 2002; 45(15) pp 3161 - 3170
7. [7]Bioorganic & Medicinal Chemistry Letters Volume 11, Issue 16, 20 August 2001, Pages 2079-2083 Petukhov, Zhang, Johnson, Tella, Kozikowski
8. [8]J. Med. Chem.; (Letter); 2004; 47(24); 5821-5824. Zhou, J.; He, R.; Johnson, K. M.; Ye, Y.; Kozikowski, A. P.
9. [9]He, R.; Kurome, T.; Giberson, K. M.; Johnson, K. M.; Kozikowski, A. P. J. Med. Chem.; (Article); 2005; 48(25); 7970-7979.
10. [10]Yuan, H.; Kozikowski, A. P.; Petukhov, P. A. J. Med. Chem.; (Article); 2004; 47(25); 6137-6143.
11. [11] John L. Musachioa, Jinsoo Honga, Masanori Ichisea, Nicholas Senecaa, Amira K. Browna, Jeih-San Liowa, Christer Halldinb, Robert B. Innisa, Victor W. Pikea, Rong Hec, Jia Zhoud and Alan P. Kozikowskic, Bioorganic & Medicinal Chemistry Letters Volume 16, Issue 12, 15 June 2006, Pages 3101-3104
12. [12]Bioorganic & Medicinal Chemistry Letters, Volume 9, Issue 23, 6 December 1999, Pages 3273-3276 Stacey A. Lomenzo, Sari Izenwasser, Robert M. Gerdes, Jonathan L. Katz, Theresa Kopajtic and Mark L. Trudell
13. [13]Lomenzo, S. A.; Rhoden, J. B.; Izenwasser, S.; Wade, D.; Kopajtic, T.; Katz, J. L.; Trudell, M. L. J. Med. Chem.; (Article); 2005; 48(5); 1336-1343.
14. [14]Bioorganic & Medicinal Chemistry Volume 13, Issue 19, 1 October 2005, Pages 5623-5634
15. United States Patent 3,813,404 Issue Date: May 28, 1974
16. Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6180648, 2001.
17. Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6472422, 2002.
18. Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6806281, 2004.
19. Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, WO9845263, 1998
20. Kozikowski; Alan P.; Araldi; Gian Luca; Tamiz; Amir P., WO0020390, 2000.
21. KOZIKOWSKI ALAN P (US); ZHOU JIA (US), WO2005041875, 2005.
22. United States Patent 6,376,673 Moldt, et al.
23. WO2004039778 Date: 2004-05-13 Inventor: WAETJEN FRANK (DK) Applicant: NEUROSEARCH AS (DK); WAETJEN FRANK (DK)