Polypharmacology of dopamine D 1-like receptor antagonists

Drug discovery based on development of selective ligands for a specific target intended to modulate its activity and revert pathophysiological process is now recognized as too simplistic to design effective agent for complex multifactorial diseases, characterized by diverse physiological dysfunctions caused by deregulations of complex networks of proteins. Major challenge in modern drug discovery is to rationally design multitarget drugs able to specifically modulate only a group of desired targets while minimizing interactions with off-targets. Multifactorial cerebral mechanisms implicated in mental (psychiatrics) and neurodegenerative diseases and interactions of the neurotransmitter systems are two main reasons for applying polypharmacology („multi-target”) strategy in drug discovery for these complex brain diseases. In this paper we review polypharmacological profile and potential therapeutic application of dopamine D1-like receptor antagonists.


Polypharmacology
Modern drug design of multitarget ligands able to specifically modulate complex networks of proteins and show unique polypharmacological profiles is becoming increasingly important in drug discovery for complex brain diseases [1][2][3][4][5].
The most significant advantages of use of multitarget drugs over the other therapeutic strategies is based on: improved efficacy as result of synergistic or additive effects caused by simultaneous and specific interactions with chosen palette of biological targets; better distribution in target tissue for simultaneous action on multiple targets; accelerated therapeutic efficacy in terms of initial onset and achievement of full effect; treatment of broader therapeutic range of symptoms; predictable pharmacokinetic profile and mitigated drug-drug interactions; lower incidence of molecule-based side effects; increased therapeutic interval of doses; better quality of treatment; improved patient compliance and tolerance; and lower incidence of developing target-based resistance as result of modulation of multiple targets [1,6,7].
Designed Multiple Ligands (DMLs) contain the primary pharmacophore elements for each target which could be separated by linker (conjugate DMLs), touched at one point (fused) or combined by using commonalities in the structures of underlying pharmacophores (merged) [7,8].Relatively rigid and small structures of highly merged DMLs result in better physicochemical, pharmacokinetic and pharmacological profile [7,8].
Based on the predicted activities on the targets and estimated pharmacokinetic profiles of designed multipotent ligands are selected the most promising candidates for further study [8][9][10][11][12].
Multifactorial cerebral mechanisms and deregulation of very complex networks of proteins implicated in mental (schizophrenia) [13,14] and neurodegenerative disorders [15], such as Parkinson's [16,17] and Alzheimer's diseases [18]), have generated intense interest in developing efficient multipotent CNS drugs [19][20][21].Interactions of the neurotransmitter systems, such as the dopamine-glutamate interaction in pathogenesis of schizophrenia and Parkinson's disease [22,23] and the serotonindopamine interaction in pathogenesis of various disorders including schizophrenia, depression, Parkinson's disease and drug abuse [24,25,26], are very important factors in design of multitargeted ligands with optimized pharmacological effects.
Therefore, a more efficient polypharmacology strategy for treatment of complex mental/neurodegenerative diseases is based on specific interactions on set of targets with minimal side effects arising from interaction with defined antitargets [1,27].
While many neurotransmitter systems contribute to the complex pathology of schizophrenia, dopamine dysfunction is considered as the basis of this disorder.The dopamine hypothesis of schizophrenia is supported by the characteristics of the drugs used to treat this disorder: all antipsychotics used clinically have high affinity for dopamine receptors [33].
Parkinson disease (PD), a neurodegenerative disorder of unknown etiology, is characterized by extensive degeneration of dopaminergic neurons within the substantia nigra, resulting in tremor, rigidity, and bradykinesia.One treatment strategy is the use of Dopamine receptor agonists, which act directly on the depleted nigrostriatal dopaminergic system and have fewer undesirable side effects than L-DOPA.Dopamine receptor agonists can be used in conjunction with lower doses of L-DOPA in a combined therapy approach [33].

Dopamine D 1 -like receptor antagonists
Five distinct GPCRs (D 1 -D 5 receptors) have been cloned and determined to mediate the actions of dopamine.The DA receptors are distinct from one another in pharmacology, amino acid sequence, distribution, and physiological function.Based on their effector-coupling profiles dopamine receptors are organized into two families, the D 1 -like (D 1 , D 5 ) and D 2 -like (D 2 , D 3 , D 4 ) receptors [33].
Dopamine D 1 receptor is predominantly found in the direct pathway of the striatonigral neurons [48,49].The main physiological function of the D 1 receptor is to mediate CNS actions of dopamine to control cognitive function [50] and movement [51,52].
The physiological processes under dopaminergic control include reward, emotion, cognition, memory, and motor activity.Dysregulation of the dopaminergic system is critical in a number of disease states, including Parkinson disease, Tourette's syndrome, bipolar depression, schizophrenia, attention deficit hyperactivity disorder, and addiction/substance abuse [33].Dopamine receptor antagonists are a mainstay in the pharmacotherapy of schizophrenia.
Mice lacking the D 1 receptor display deficits in multiple forms of memory, such as impaired spatial memory and deficits in prefrontal cortex-dependent working memory.Therefore the pharmacological evidence that cortical working memory can be modulated with D 1 agonists and antagonists is in agreement with the previous findings [33].
Since D 1 and D 5 receptors possess about 80% homology in their transmembrane domains these two receptors are grouped as D 1 -like receptors.Pathophysiology of schizophrenia and related diseases is mainly based on dysfunctions in dopamine, serotonin, and glutamate, [33,53,54].However, selective D 1 antagonism alone is not accepted as effective antipsychotic principle [55,56].Therapeutic effects of typical and atypical neuroleptics are mostly mediated by inhibition of dopamine D 2 -like receptors (D 2 and D 4 receptors) and other related aminergic receptors [33].Blockade of dopamine D 2 and serotonin 5-HT 2A receptors is mainly responsible for antipsychotic effect [57], while interaction with various dopamine (D 1 , D 3 , D 4 ), serotonin (5-HT 1A , 5-HT 1D , 5-HT 2A , 5-HT 2C ), and histamine H 3 receptors may produce additional antipsychotic or procognitive effects [54,58,59].Moderate antagonistic activity at D 1 -receptors of atypical antipsychotic clozapine is suggested to be responsible for its effectiveness against treatment-resistant schizophrenia [55].
As a selective antagonist, 1 (SCH 23390) has been extensively used for the clarification and better understanding of the role of the D 1 receptors in various CNS disorders.
Examination of the pharmacologic profile of 1 (SCH 23390) covered its effects on motor behavior and memory, as well as in vivo anticonvulsant studies.The anticonvulsant properties of 1 (SCH 23390) indicated on the importance of D 1 dopaminergic receptor in initiation of generalized seizures.The available pharmacokinetic data of this compound suggest that after oral administration it undergoes extensive first-pass metabolism and has short half-life of around 25 minutes following administration of 0.3 mg/kg i.p. in the rat and therefore could not be further developed as a drug [63,64].Even the longer acting analogue 2 (SCH 39166) [61] showed very low oral bioavailability (0.6%).Pharmacokinetic studies has discovered that extensive O-glucuronidation of the phenol and N-dealkylation of the N-Me group of the 1 (SCH 23390) and 2 (SCH 39166) may contribute to the poor pharmacokinetic (PK) profile [69][70][71].
Since the discovery of the 1 (SCH 23390), many dopamine D 1 receptor ligands possessing phenyltetrahydrobenzazepines scaffold have been synthesized and analyzed.In particular, D 1 antagonistic activity of this chemical group of compounds is determined by the nature of C-7 substituent, such as chlorine in the 1 (SCH 23390) or bromine in the SKF R-83566 [72,73].
The two series of 1,3-benzodiazepine based D 1 antagonists, the cyclic N-aryl amidine and the cyclic N-aryl guanidine, was designed following a pharmacophore models derived from catecholamine analog 1 (SCH 23390).By replacing benzazepine core with 1,3-benzodiazepine, metabolically labile N3-methyl group presented in 1 (SCH 23390) was eliminated while basicity of new model systems, with pK a values of 8-9 and 10-11 for N-aryl amidine and N-aryl guanidine respectively, stayed within same range as those for the tert-azepine nitrogen center in 1 (SCH 23390).Among N1arylbenzodiazepines the highest affinity for D 1 receptor was observed with 3-thienyl substituent 3 [74], K i = 87 nM) while within cyclic N-aryl guanidines stronger basicity did not result in improved D 1 receptor binding affinity 4 (Figure 1) [75], K i = 129 nM) [74].
A highly potent D 1 /D 5 antagonists 5 [75]) possessing subnanomolar D 1 affinity and high selectivity over D 2 receptor were synthesized by introducing a series of bulky substituents at the para position of the pendant phenyl ring in 1 (SCH 23390).The obtained results indicate that the para position has a high steric tolerance for substitution [75].
Despite of their cyclic structure the benzazepines possess a considerable degree of conformational mobility and it is considered that equatorial orientation of the phenyl ring is optimal for interaction with the D 1 receptor [61].
The preparation of conformationally restricted analogues of the 1 (SCH 23390) resulted in new series of 6,6a,7,8,9,13b-hexahydro-5H-benzo [d] naphtho [2,l-b] azepines having the B and C rings junction in two possible configurations, B/C-cis and B/C-trans.Binding studies of the B/C-cis and B/C-trans series of compounds clearly demonstrated that conformationally rigid trans series, where the D ring is unequivocally fixed in an equatorial orientation, possess significantly higher D 1 receptor affinity and selectivity over the D 2 receptor.From this investigation were derived highly selective D 1 receptor antagonist which (-)-6aS,13b R isomer (2 (SCH 39166) ) has the highest D 1 affinity (K i = 1.9 nM for D 1 and 514 nM for D 2 ).This finding is consistent with the fact that the D 1 receptor activity in the 1-phenyl-1H-3-benzazepine series is associated with the R-enantiomers [61]. 2 (SCH 39166), also known as ecopipam, has been in clinical trials for several diseases including obesity [76], cocaine addiction [77] schizophrenia [78].Although 2 (SCH 39166) possess high D 1 -like selectivity with reduced affinity for serotonin receptors and longer duration of action in primates in comparison to 1 (SCH 23390), both compounds displayed low oral bioavailability [79].
Various 1 (SCH 23390) and 2 (SCH 39166) analogues were synthesized and evaluated as selective dopamine D 1 /D 5 receptor antagonists.Some of these trials include investigation of the phenol bioisosteric analogues of 1 (SCH 23390) and 2 (SCH 39166), such as benzotriazole, indole, benzimidazole, benzimidazolone and benzothiazolone.The designed corresponding heterocyclic systems, containing an N-H hydrogen bond donor group, retained the characteristic of the phenol group that are thought to be responsible for interaction with the receptor.Benzotriazole analogue of 2 (SCH 39166), 6 (Figure 1) [68]), displayed very low affinity for D 1 receptor (K i = 583 nM) suggested that conformer A was not the active binding conformer.In comparison with 6 [68], indole analogue of 2 (SCH 39166) 7 [68] displayed appreciable affinity for D 1 receptor.Further optimization of the hydrogen bond donating properties of different heterocyclus analogues of conformer B also indicated the preference of conformation B over A, whereby hydrogen-bond donating directionality has been established.Among the designed compounds highly selective D 1 /D 5 antagonists, benzimidazolone analogue (8 [68], K i = 7 nM for D 1 and 4.2 nM for D 5 ) and its corresponding NH benzazepine (9 [68], K i = 16.5 nM for D 1 and 2.4 nM for D 5 ) together with benzothiazolone analogue (10 [68], K i = 2.1 nM for D 1 , 2.8 nM for D 5 ) and its corresponding NH benzazepine (11 [68], K i = 6.5 for D 1 and 1.7 for D 5 ) were of particular interest in terms of their overall profiles (Figure 1).Improved pharmacokinetic profiles of heterocyclic isosteres demonstrated by rats plasma levels is associated with higher metabolic stability with respect to O-glucuronidation.In contrast, biological evaluation of phenol bioisosteric analogues of 1 (SCH 23390) revealed huge decrease in the D 1 binding affinity with exception of 12 [68] which was identified as a potent D 1 /D 5 ligand in this series but without significant improvement in pharmacokinetic profile compared to 1 (SCH 23390).This finding indicated that molecular rigidity might play important role in improving the pharmacokinetic properties [68].
Besides this series of benzodiazepines, derivatives of alkaloids such as boldine, predicentrine and l-(S)-stepholidine have been synthesized and examined as potential D 1 -ligands [81,83].

Conclusion
Based on the results of the studies novel selective D 1 /D 5 antagonists, 8, 9 10, 11, and 12 [68], were of particular interest in terms of their overall binding profiles for dopamine D 1 /D 5 receptors and α 2A -AR, improved pharmacokinetic properties compared to their leads 1 (SCH 23390) and 2 (SCH 39166), and moderate binding affinity to the