One of the prototypical dopamine-receptor agonists is (6aR)-(-)-apomorphine (la).
In fact, h s semi-synthetic compound was the first compound shown to mimic potently the action of dopamine [170]. (6aR)-(-)-Apomorphine (la), which bears the dopamine moiety in its a-rotameric conformation,* is generally considered as a mixed DllD2- receptor agonist. However, close examination of its pharmacological effects showed that this compound acts as a full agonist at the D2 receptor, while it behaves as a partial agonist at the D l receptor [171]. Additional studies showed that its affinity at the D2 receptor is several times higher than at the Dl receptor 11721. Originally, the optical antipode (lb) was shown to be inactive as a dopamine-receptor agonist [173]. Later studies revealed that this compound acts as a weak antagonist at the D l receptor as well as the D2 receptor [171]. In contrast, both enantiomers of isoapomorphine (2a,b),
* In 1975 Cannon proposed that dopamine might interact with its receptors in the two possible conformational extremes of the trans coplanar form, which he designated as the a- and P-rotameric conformations. In both rotamers the ethylamine side chain displays coplanarity with the aromatic ring and possesses an extended conformation. In the a-rotamer the meta-hydroxyl group is projected over the ethylamine side chain, whereas in the p-rotamer the meta-hydroxyl group is directed away from the ethylamine side chain [ I 5,163-1651.
OH a-rotamer
Chart 1.3 Chemical structures of (6aR)-(-)-apomorphine (la), (6aS)-(+)-apomorphine (lb), (6aR)- (-)-isoapomorphine ( 2 4 , and (6aS)-(+)-isoapomorphine (2b).
containing the dopamine moiety in its p-rotameric conformation, are inactive as dopamine-receptor agonists or antagonists [174,175].
SAR-studies on analogues of (R)-(-)-apomorphine (la) revealed that (R)-(-)-N-n- propylnorapomorphine (3), (R)-(-)- 1 l-hydroxyaporphine (4) and (R)-(-)- 1 1 -hydroxy- N-n-propylnoraporphine (5) are potent dopamine-receptor agonists. The last two com-
Chart 1.4 Chemical structures of (R)-(-)-apomorphine analogues (3-5)
pounds contain only a meta-hydroxyl group.
In
contrast to (R)-(-)-apomorphine (la), (R)-(-)-N-n-propylnorapomorphme (3) acts as a full agonist at both dopamine-receptor subtypes [171]. Moreover, both N-propyl analogues (3,s) possess more than a 10-fold higher a f f i t y at the D2 receptor than (R)-(-)-apomorphine (la), while the affinity at the D l receptor stays almost the same [172,176]. In this respect, several 2-substituted analogues of (R)-(-)-N-n-propylnorapomorphine (3), such as (R)-(-)-2-hydroxy-N-n- propylnorapomorphine (6) and (R)-(-)-2-fluoro-N-n-propylnorapomorphine (7), are highly selective D2-receptor agonists [177,178]. Particularly, (R)-(-)-2-fluoro-N-n- propylnorapomorphine (7) has the highest D2-receptor affinity and D2/D1-receptor selectivity of any agent yet described [179]. Recently, it was also shown that (R)-(-)- I 1 -hydroxyaporphine (4) acts as an antagonist at the D 1 receptor, while it acts as an agonist at the D2 receptor. In fact, all of the (R)-(-)-1 l-monohydroxyaporphmes studied, such as the 10-bromo analogue (8), behave as Dl-receptor antagonists [180].Chart 1.5 Chemical structures of (R)-(-)-2-hydroxy-N-n-propylnorapomorphie (6), (R)-(-)-2-fluoro- N-n-propylnorapomorphine (7), and (R)-10-bromo-1 1-hydroxyaporphine (8).
Another prototypical dopamine-receptor agonist is (25)-(-)-5,6-dihydroxy-2-(N,N- di-n-propy1amino)tetralin (9). It is not only a chiral congener of the fkagment of (6aR)- (-)-apomorphine (la), believed to be responsible for its dopamine-like activity, but also a cyclic, semi-rigid analogue of dopamine in its a-rotameric conformation [ 15,164,165, 167,1691. This optical-active 2-aminotetralin derivative acts as a very potent mixed DlKI2-receptor agonist with full intrinsic efficacy at both subtypes of dopamine receptors. The (2R)-(+)-enantiomer is much less active as dopamine-receptor agonist. In sharp contrast, the (2R)-(+)-enantiomer of the isomeric, dopamine P-rotamer-containing 6,7-dihydroxy-2-(N,N-di-n-propy1amino)tetralin (lo), which displays also prominent dopamine-receptor agonism, is more active than its (28-(-)-optical antipode.
Chart 1.6 Chemical structures of (29-(-)-5,6dihydroxy-2-(N,Ndi-n-propy1o)rain (9), (2R)- (+)-6,7-dihydroxy-2-(N,N-di-n-propyl- (lo), (29-(-)-5 -hydroxy-2-(N,N-di-n- propy1amino)tetralin (ll), and ( 2 R ) - ( + ) - 7 - h y d r o x y - 2 - ( N , N - d i - n - p r o p y l ~ l i n (12).
Figure 1.5 Interaction of chiral agents with McDermed's dopamine-receptor model.
This stereochemical difference has been elegantly rationalized by McDermed and colleagues [181a]. They suggested that when these and related chiral agonists bind at dopamine receptors, the steric orientation required of the amino group of the agonist is controlled primarily by the location of the hydroxyl group, positioned meta to the ethylamine side chain. This implies that dopamine-receptor agonists, bearing the dopamine moiety in its a-rotameric conformation, such as (6aR)-(-)-apomorphine (1 a) and (2S)-(-)-5,6-dihydroxy-2-(N,N-di-n-propylo)teal (9), and dopamine- receptor agonists, bearing the dopamine moiety in its p-rotameric conformation, such as (2R)-(+)-6,7-dihydroxy-2-(N,N-di-n-propylamino)tetralin
(lo),
must be flipped and rotated, as illustrated in Figure 1.5, in order to achieve a proper orientation of the amino group and the meta-hydroxyl group with respect to their presumed complimentary binding sites on dopamine receptors. To account for the inactivity of (6aS)-(+)- isoapomorphine (2b) at dopamine receptors, McDermed and colleagues suggested also that dopamine receptors include a steric boundary preventing the interaction with compounds possessing steric bulk in this region (Figure 1.5). A similar dopamine- receptor model was proposed by Grol and colleagues [18 lb, 18 lc]. In the course of time McDermed's dopamine-receptor model was extended by Wikstrom and colleagues, who provided an explanation for the relationship between the absolute configuration, the ring position of the meta-hydroxyl group and the permissible size of the N-alkyl substituent in rigid chiral dopamine-receptor agonists [168,182]. Additionally, Seiler and Markstein suggested steric barriers and accessory binding sites to differentiate between the binding at the two subtypes of dopamine receptors [169,183].Pharmacological studies with monophenolic 2-(N,N-di-n-propy1amino)tetralins revealed (2S)-(-)-5-hydroxy-2-(N,N-di-n-propylamh&tdh (1 1) as the most potent dopamine-receptor agonist in this series, followed by the (2R)-(+)-7-hydroxy analogue
(12) [169,184,185]. The stereochemical difference can be rationalized by McDemed's dopamine-receptor model. Compared with the (25')-(-)-enantiomer of the 5,6-dihydroxy analogue (9), (25')-(-)-5-hydroxy-2-(N,N-di-n-propylamino)tetralin (1 1) displays an increased D2/D 1-receptor selectivity. Thls observation in combination with the fact that RU 24213 (17) acts as a selective D~receptor agonist (see below) laid the foundation for the development of the selective D~receptor agonists N-0434 (13) and N-0437 (14), 5-hydroxy-2-aminotetralins, of which the (29-(-)-enantiomers are the more active ones [186-1911. Moreover, (2R)-(+)-N-0437 behaves pharmacologically as a selective D2- receptor partial agonist [192]. Additionally, 2-aminotetralins exist which interact relatively selectively with the D 1-receptor [193]; the relatively selective D 1-receptor agonist 8-chloro-6,7-dihydroxy-2-aminotetralin (15) was developed on the basis of the Dl-receptor activity of 6-halogen substituted benzazepines (see below).
Chart 1.7 Chemical structures of N-0434 (13), N-0437 (14), 8-chloro-6,7-dihydroxy-2-aminotetralin (IS), and TL 99 (16).
Analysis of the overall pharmacological effects of 2-aminotetralins showed that those bearing a 7-hydroxyl group, such as 7-hydroxy-2-(N,N-di-n-propy1amino)tetralin (12) and TL 99 (16), exhibit apparent selectivity for dopamine autoreceptors (see 1.2.3) [194-1961. Recently, these two aminotetralins were also shown to be D3-receptor agents of high affinity (subnanomolar range) and moderate selectivity (almost 100- and 20- fold, respectively, with respect to the D2 receptor) [136,144,145]. As expected, the D3 receptor displays, in relation to Zaminotetralins, the same enantioselectivity as the D l and the D2 receptor, i.e, the (2R)-(+)-enantiomer of 7-hydroxy-2-(N,N-di-n-propyl- amino)tetralin (12) is a better D3-receptor agent than its optical antipode [197,
198a,198b]. Interestingly, (2R)-(+)-7-hydroxy-2-(N,N-di-n-propylamh)~mh (12) decreases dopamine release at doses well below its affinity at the D2 receptor [198a, 198bl. Therefore, this biochemical effect may, at least in part, be a consequence of D3- autoreceptor activation. In addition, this compound induces at very low doses yawning and reduces at the same doses spontaneous activity including locomotion [198a-198~1.
These behavioural effects caused also by low doses of dopamine-receptor agonists, such as (6aR)-(-)-apomorphine (la), are believed to be mediated via inhibitory postsynaptic dopamine receptors [199]. Thus, yawning and inhibition of spontaneous activity may involve the stimulation of an inhibitory D3-heteroreceptor [198a-198dl.
Beside the apomorphines (R)-(-)-2-hydroxy-N-n-propylnorapomorphie (5) and (R)-(-)-2-fluoro-N-n-propylnorapomorphine (6) and the 2-aminotetralins (29-(-)-N- 0434 (13) and (2S)-(-)-N-0437 (14), other well-known selective D2-receptor agonists are the phenethylamines RU 24213 (17) and RU 24926 (18), the tricyclic partial ergoline analogues quinpirole (LY 17 1555, 19) and quinelorane (LY 163502, 20), and the hexahydronaphthoxazine (+)-PHNO ((+)-N-0500, 21) [200-2101. Recently, it was shown that quinpirole (19), quinerolane (20) and (+)-PHNO (21) display higher affinities at the D3 receptor than at the D2 receptor [136,144,211].
Chart 1.8 Chemical structures of the selective D2-receptor agonists RU 24213 (17), RU 24926 (18), quinpirole (19), quinelorane (20), and (+)-PHNO (21).
During the last decade many agents allegedly presumed to be selective D2- autoreceptor agonists were identified. Examples of this class of compounds, besides TL 99 (16) [194], are (5)-(-)-3-PPP (preclamol, 22), B-HT 920 (talipexole, 23), SND 919 (prarnipexole, 24), (5')-(-)-PD 128483 (25), PD 128907 ((+)-PTBO, 26), EMD 23448 (27), and PD 143188 (28) [79,80,87,212-2181. Detailed analysis of their pharmaco- logical profiles revealed that all these compounds act selectively as partial agonists at D2 receptors and that the magnitude of their intrinsic efficacy at these dopamine receptors varies not only with the location of these receptors [postsynaptic versus presynaptic], but also with the conditions chosen [postsynaptically: normosensitive versus supersensitive (e.g. induced by 6-OHDA lesioning or prolonged reserpinization)]
[87]. For example, (8-(-)-3-PPP (22), EMD 23448 (27), and B-HT 920 (23) behave essentially as an antagonist, a partial agonist of moderate intrinsic efficacy, and an almost full agonist at normosensitive postsynaptic D2 receptors, respectively. Never- theless, (5')-(-)-3-PPP (22) acts as a partial agonist of moderate intrinsic eficacy at presynaptic D2 receptors and EMD 23448 (27) as well as
B-HT
920 (23) act as full agonists at these dopamine receptors, while all display agonist activity at supersensitiveChart 1.9 Chemical structures of the putative selective Dl-autoreceptor agonists (a-(-)-3-PPP (22), B-HT 920 (23), SND 919 (24), (5')-(-)-PD 128483 (25), PD 128907 (26), EMD 23448 (27), and PD 143188 (28).
postsynaptic D2 receptors (6-OHDA-denervation in rats). Thus, it was proposed that the apparent D2-autoreceptor selectivity of these agents stems from their intrinsic efficacies at D2 receptors rather than their absolute affmities for presynaptic versus postsynaptic D2 receptors and that it is better to rank D2-receptor agonists according to gradually increasing agonist efficacy rather than to classify into autoreceptor-selective versus nonautoreceptor-selective D~receptor agonists [219]. Interestingly, PD 128907 ((+)- PTBO, 26) was identified very recently as a D3-receptor agent of high affinity (low nanomolar range) and high selectivity (approx. 1500-fold with respect to the D2 receptor) [2 1 1, 2201.
The first known dopamine-receptor agonist interacting selectively with the D l receptor was the benzazepine SKF 38393 (29) [2211; its Dl-receptor agonist activity resides almost exclusively in the (R)-(+)-enantiomer [222]. However, this compound displays moderate Dl-receptor affinity and is just a selective Dl-receptor partial agonist of moderate intrinsic efficacy [223-2251; its intrinsic efficacy appears to be among other things species-dependent (lower in primate than in rodent striatum) [226,227]. SAR- studies revealed that N-alkylated (30,31) as well as 6-halogenated analogues (32,33) of (R)-SKF 38393 (29) display higher affinities at the Dl receptor than (R)-SKF 38393 (29). However, these benzazepines still act as Dl-receptor partial agonists [223-225, 2281. Additional SAR-studies revealed that (R)-SKF 82958 (Cl-APB, 34), the N-allyl-6- chloro analogue of (R)-SKF 38393 (32), combines high amity at the Dl-receptor with
\ N-H
HO HO HO
Chart 1.10 Chemical structures of the benzazepines (R)-SKF 38393 (29), (R)-SKF 75670 (30), (R)- SKF 77434 (Lu 24-040, 31), (R)-SKF 81297 (32), (R)-SKF 80723 (33), and (R)-SKF 82958 (34).
high intrinsic efficacy at this receptor (almost full agonism in primate as well as rodent striaturn) [224,227,229]. An additional advantage of (R)-SKF 82958 (34) is its higher in vivo CNS potency; this benzazepine crosses more readily the blood-brain barrier than N-unsubstituted benzazepines owing to its higher lipophilicity.
Lately, selective Dl-receptor agonists belonging to other chemical classes than the benzazepine class have been identified. Presently available Dl-receptor agonists are for example the tetrahydroisoquinoline DPTI (35), the tetrahydrothienopyridine SKF 89626 (36), the hexahydroindolophenanthridine or "benzergoline" CY 208-243 (37), the hexahydrobenzophenanthridine DHX (dihydrexidine, SDZ 2 10-7 12, 38), and the 1- arninomethylisochroman A-77636 (39) [169,225,227,230-2381. The bioisosteric agents DPTI (35) and SKF 89626 (36) display both full agonism at the D l receptor [225,230, 2311. However, these two selective Dl-receptor agonists possess a weak ability to penetrate the blood-brain barrier. The benzergoline CY 208-243 (37) is only a selective Dl-receptor partial agonist [169,225,227,232,233]. In contrast, DHX (38) is a full eff~cacy Dl-receptor agonist of high potency [169,234-2361. However, this agent exhibited only moderate selectivity towards the D2 receptor 12351. Recently, the 4- methyl-N-n-propyl analogue of DHX (MPDHX, 40) was shown to be a Dyreceptor agent of high a m i t y and the same D3fD2-receptor selectivity as the present prototypical Dyreceptor agent 7-hydroxy-2-(N,N-di-n-propyl-amino)tetralin (12) [239].
A-77636 (39) is a potent, full efficacy Dl-receptor agonist, which displays approxi- mately a 30-fold DlDI2-receptor selectivity [237,238]. Advantageously, A-77636 (39) is orally active, although not potently, and long-acting. The reasons for the long duration of action are not well understood, particularly in the light of the fact that catecholamines are notorious for being rapidly metabolized. One possible explanation is that A-77636 (39) readily crosses the blood-brain barrier protecting it from peripheral metabolism. For this hypothesis to be true, this compound would have to be sequestered in the brain, and more importantly, not to be a good substrate for metabolic enzymes in the CNS.
Chart 1.11 Chemical structures of the selective Dl-receptor agonists DPTI (35), SKF 89626 (36), CY 208-243 (37), DHX (38), and A-77636 (39) as well as the selective Dg-receptor agent MPDHX (40).