Trihexyphenidyl

Non-selective Muscarinic Acetylcholine Receptor Antagonism

This compound acts as a non-selective antagonist of all five subtypes of muscarinic acetylcholine receptors (M1-M5). drugbank.comnih.gov This broad antagonism means that it blocks the action of the neurotransmitter acetylcholine at these receptors throughout the central and peripheral nervous systems. wikipedia.orgpatsnap.com The binding affinities of this compound to these receptor subtypes vary, with research indicating low nanomolar affinity across all five. nih.gov

Selective Antagonism at M1 and M4 Muscarinic Receptors

Despite its non-selective nature, this compound demonstrates a higher antagonistic activity at the M1 and M4 muscarinic acetylcholine receptors. wikipedia.orgdrugbank.com This has led to its description as being selective for these particular subtypes. wikipedia.orgmedchemexpress.com The affinity for M1 receptors, which are abundant in the cerebral cortex and striatum, is particularly high. patsnap.comdrugbank.comnih.gov Studies have shown that the (R)-enantiomer of this compound displays high affinities for both m1 and m4 receptors. researchgate.netnih.gov This selectivity for M1 and M4 receptors is considered a key aspect of its therapeutic efficacy in movement disorders. patsnap.com

Table 1: Binding Affinities of this compound for Muscarinic Receptor Subtypes

Data sourced from a study by Dorje et al. (1991) and Bolden et al. (1992) as cited in a 2019 study. nih.gov

Inhibition of Efferent Impulses in Parasympathetically Innervated Structures

This compound exerts a direct inhibitory effect on the parasympathetic nervous system. medlink.comnih.govmedicines.org.ukpediatriconcall.com This action blocks the efferent impulses in structures that are innervated by parasympathetic nerves. wikipedia.org The result is a relaxation of smooth muscle tissue, which is achieved both through a direct action on the muscle itself and indirectly via the inhibition of the parasympathetic nervous system. medlink.comnih.govpediatriconcall.com

Indirect Enhancement of Dopamine Release in the Striatum via Nicotinic Acetylcholine Receptor Modification

Research suggests that this compound can indirectly enhance the release of dopamine in the striatum. drugbank.com This effect is thought to be mediated through the modification of nicotinic acetylcholine receptor neurotransmission. drugbank.comnih.gov Studies in mouse models have shown that this compound increases striatal dopamine release and that this action is dependent on functional nicotinic receptors. nih.govnih.gov This indirect dopaminergic activity may contribute to its therapeutic effects in conditions characterized by dopamine deficiency, such as Parkinson's disease. patsnap.com

Potential Binding to Dopamine Receptors

There is also evidence to suggest that this compound may directly bind to dopamine receptors. wikipedia.orgmdpi.comresearchgate.netijiapp.com At higher concentrations, its affinity for dopaminergic receptors is thought to be responsible for some of its neuropsychiatric effects. mdpi.comresearchgate.net This potential interaction with dopamine receptors adds another layer of complexity to its neuropharmacological profile. ijiapp.com

Table 2: Summary of this compound's Neuropharmacological Actions

Psychostimulant-like Effects and Dopamine Signaling

Recent studies suggest that this compound exhibits psychostimulant-like properties that may be mediated through its influence on dopamine signaling. oaji.netresearchgate.net Research in animal models has demonstrated that this compound can increase locomotor activity, a behavioral marker often associated with psychostimulants that enhance dopamine transmission. oaji.net This effect was dose-dependent and could be prevented by pretreatment with olanzapine, an antagonist of dopamine receptors, further implicating the dopaminergic system in this compound's stimulant-like actions. oaji.netresearchgate.net

Furthermore, in the forced swim test, a model used to assess antidepressant-like effects, this compound was found to decrease immobility time in mice. oaji.netresearchgate.net This outcome is consistent with the actions of many antidepressant medications that enhance monoamine signaling, particularly dopamine. oaji.net While the primary therapeutic action of this compound is attributed to its anticholinergic properties, these findings suggest a potential indirect or direct modulation of dopamine neurotransmission. oaji.netresearchgate.net Some evidence points towards the possibility that by blocking inhibitory muscarinic M4 receptors on midbrain dopamine neurons, this compound could indirectly increase their activity and subsequent dopamine release. oaji.net Other studies propose that this compound may also modify nicotinic acetylcholine receptor neurotransmission, which in turn could lead to an indirect enhancement of dopamine release in the striatum. drugbank.comnih.govnih.gov

Inhibition of Hippocampal Glutamatergic Synaptic Transmissions

Research has shown that this compound can inhibit action potential-dependent glutamatergic synaptic transmission between hippocampal neurons. nih.gov Specifically, it has been observed to suppress the frequency of excitatory postsynaptic currents (EPSCs) in primary hippocampal cultures. nih.govresearchgate.netnih.gov This inhibitory effect on glutamatergic transmission is significant as overstimulation of this system is a key factor in the sustenance of seizures. researchgate.net The concentration-response relationship for this suppression yielded an IC50 value of approximately 6.3 µM. nih.govresearchgate.netresearchgate.net Interestingly, this inhibition of synaptic transmission by this compound appears to occur through a mechanism that is independent of N-methyl-D-aspartate (NMDA) receptor, muscarinic acetylcholine receptor (mAChR), and α7 nicotinic acetylcholine receptor (nAChR) inhibition. nih.govresearchgate.netnih.gov

Inhibition of Hippocampal GABAergic Synaptic Transmissions

Concurrently with its effects on the glutamatergic system, this compound also inhibits action potential-dependent GABAergic synaptic transmissions in the hippocampus. nih.gov It reduces the frequency of inhibitory postsynaptic currents (IPSCs) recorded from cultured hippocampal neurons. nih.govresearchgate.netnih.gov The suppressive effect on both glutamatergic and GABAergic transmissions is likely mediated by a single mechanism of action, as the concentration-response relationships for both are overlapping and can be described by a single sigmoidal function. nih.gov The IC50 for the reduction in both EPSC and IPSC frequencies was found to be approximately 6.3 µM. nih.govresearchgate.netresearchgate.net Importantly, this compound did not affect the probability of transmitter release, as it had no effect on the frequency of miniature IPSCs and EPSCs, nor did it alter the activity of postsynaptic GABAA and glutamate receptors. researchgate.netnih.govresearchgate.net

Role in Organophosphorus-Induced Acetylcholinesterase Inhibition and Seizures

The inhibitory effects of this compound on glutamatergic and GABAergic systems are particularly relevant in the context of organophosphorus (OP)-induced neurotoxicity. Acute exposure to OP compounds leads to the inhibition of acetylcholinesterase (AChE), causing an accumulation of acetylcholine and subsequent cholinergic crisis, which includes severe and prolonged seizures. researchgate.netnih.govcdnsciencepub.com While these seizures are initiated by muscarinic receptor hyperstimulation, they are sustained by glutamatergic hyperexcitation. researchgate.net

Preclinical studies have indicated that this compound is more effective than atropine in counteracting the seizures and neuropathology triggered by OP-induced AChE inhibition. researchgate.netnih.gov This enhanced efficacy has been attributed to its ability to block both mAChRs and NMDA-type glutamatergic receptors. researchgate.netnih.gov By inhibiting the overstimulated glutamatergic synaptic transmission, this compound helps to control the seizures that are a devastating consequence of OP poisoning. researchgate.net Animal studies have suggested that antimuscarinics with additional antagonistic activity at NMDA receptors, such as this compound, are effective in blocking OP-induced seizure activity. researchgate.net

Plasma Protein Binding Characteristics

Role of Enterohepatic Circulation

Enterohepatic circulation is a process where substances are metabolized in the liver, excreted into the bile, and subsequently reabsorbed from the small intestine back into the portal circulation. slideshare.net For this compound, research indicates that its involvement in enterohepatic circulation is minimal. nih.govsmolecule.com This suggests that once excreted into the bile, the compound is not significantly reabsorbed into the bloodstream for further circulation.

Idiopathic Parkinson's Disease

In the management of idiopathic Parkinson's disease, this compound can be used as an initial monotherapy, particularly in younger patients where tremor is the predominant symptom. drugs.com It is also frequently used as an adjunctive therapy to levodopa. rxlist.commedscape.comnih.gov The drug has been shown to provide a substantial alleviation of symptoms, although it does not cure the disease. wikipedia.org

Postencephalitic Parkinsonism

This compound is effective in treating postencephalitic parkinsonism. medscape.comcambridge.orgnih.gov Patients in this subgroup may sometimes require and tolerate higher daily doses of the medication to achieve optimal symptom control compared to those with other forms of parkinsonism. rxlist.comcambridge.org

Arteriosclerotic Parkinsonism

The use of this compound is also indicated for arteriosclerotic parkinsonism. medscape.comcambridge.orgnih.gov As with other forms of parkinsonism, it helps in managing the characteristic motor deficits.

Adjunctive Therapy with Levodopa and Dopamine Agonists

This compound is often used as an adjuvant therapy in combination with levodopa, the standard treatment for Parkinson's disease. rxlist.commedscape.comnih.gov This combination can be beneficial as it provides an alternative mechanism of action by suppressing cholinergic activity. researchgate.net When used with levodopa, the dosages of both drugs may need to be adjusted to optimize symptom control and manage side effects. cambridge.orgdrugs.com

Combination therapy may also include dopamine agonists, such as pramipexole and ropinirole, as part of a multi-faceted approach to treatment. medscape.comwikipedia.org Research in animal models has shown that this compound can have differential interactions with various dopamine receptor agonists. nih.gov For instance, one study observed that this compound potentiated the effects of a D1 agonist while reducing the effects of a D2 agonist. nih.gov

Symptomatic Improvement Rates and Predictors of Response

Clinical experience suggests that a significant percentage of patients with Parkinson's disease respond positively to this compound. It is estimated that 50-75% of individuals experience a 20-30% improvement in their symptoms. wikipedia.org The medication is particularly noted for its effect on tremor, though it also helps with rigidity and bradykinesia. cambridge.orgnih.gov

A study comparing the effectiveness of this compound and levodopa on motor symptoms in Parkinson's disease patients found that both drugs led to significant improvements. researchgate.net The most substantial improvement with this compound was seen in the tremor sub-score, which was comparable to the improvement seen with levodopa. researchgate.netresearchgate.net

Table 1: Comparison of Symptom Improvement with this compound vs. Levodopa

Data sourced from a comparative study on motor symptom improvement. researchgate.net

Predictors for a better response to this compound for tremor include having a milder baseline tremor severity. researchgate.netresearchgate.net Conversely, factors that may predict a higher risk of cognitive side effects, suggesting a need for caution with anticholinergic medications like this compound, include advanced age (over 70), male sex, history of falls or freezing, bilateral disease onset, and the presence of mild cognitive impairment. nih.gov

Antipsychotic-Induced Parkinsonism and EPS

This compound is frequently utilized to manage extrapyramidal side effects (EPS) that arise from treatment with antipsychotic medications, particularly first-generation agents like haloperidol, fluphenazine, and chlorpromazine. nih.gov These drug-induced movement disorders manifest as symptoms resembling Parkinson's disease, including tremors, rigidity, and bradykinesia (slowness of movement). medicinenet.compatsnap.com The therapeutic action of this compound in this context is attributed to its ability to counteract the relative excess of acetylcholine that occurs due to the dopamine blockade caused by antipsychotics. patsnap.com

Research indicates that this compound can provide significant symptomatic relief for patients experiencing these side effects. wikipedia.org It is often used as an adjunctive therapy to manage muscle stiffness, spasms, and poor muscle control. nih.govpatsnap.com However, prophylactic use of this compound to prevent drug-induced parkinsonism during neuroleptic therapy is not recommended. nih.gov Studies have shown that while effective, this compound is not a first-line treatment for idiopathic Parkinson's disease, having been largely replaced by medications like levodopa. drugbank.com

In comparative studies, this compound's efficacy has been weighed against other agents. For instance, a double-blind, crossover study comparing it with amantadine for neuroleptic-induced parkinsonism found both drugs to be equivalently effective. dovepress.compsychiatryonline.org Another study noted little difference in efficacy between this compound and benztropine for this indication. mdpi.com

Specificity for Dystonia, Akathisia, and Oculogyric Crises

This compound has demonstrated utility in treating specific and often distressing extrapyramidal symptoms:

Dystonia: This condition involves sustained or intermittent involuntary muscle contractions causing twisting and repetitive movements or abnormal postures. cochranelibrary.com this compound is used to manage acute dystonic reactions, which can appear shortly after initiating antipsychotic treatment. psychopharmacologyinstitute.com It is believed to work by reducing acetylcholine's effect in the basal ganglia, a key area for motor control. cochranelibrary.com

Akathisia: Characterized by a subjective feeling of inner restlessness and a compelling urge to move, akathisia is a common side effect of antipsychotic drugs. arizona.edu While beta-blockers are often considered first-line treatment, anticholinergic agents like this compound may be considered, particularly if parkinsonian symptoms are also present. cambridge.orgnih.gov However, its use in older adults for akathisia is generally not recommended due to potential side effects. arizona.edu

Oculogyric Crises: These are a form of acute dystonia characterized by a sustained, involuntary upward deviation of the eyes. bioline.org.br Centrally acting anticholinergics, including this compound, are a mainstay in the management of these episodes. nih.gov However, in some cases of olanzapine-induced oculogyric crisis, this compound has been reported to be ineffective, necessitating a change in the antipsychotic medication. bioline.org.br

Essential Tremor Research

While the primary focus of this compound has been on parkinsonism and dystonia, its anticholinergic properties suggest a potential role in managing other types of tremors. Essential tremor is a common movement disorder, but specific research on the efficacy of this compound for this condition is less extensive compared to its other indications. Anticholinergics, in general, may help reduce tremor, but their use is often limited by side effects. parkinsons.org.uk

Dystonia in Cerebral Palsy: Efficacy and Limitations

This compound is often used off-label to treat dystonia in individuals with cerebral palsy (CP), a condition characterized by motor problems and movement disorders. cochranelibrary.compediatriconcall.com The rationale is to reduce the involuntary muscle contractions and improve function. cochranelibrary.com

However, the evidence for its effectiveness in this population is mixed and requires careful consideration. A Cochrane review concluded that there is currently insufficient evidence to definitively say whether this compound is an effective treatment for dystonia in people with CP. cochranelibrary.comnih.gov The review found no clear evidence that it reduces dystonia or improves upper limb function. cochranelibrary.com Some studies suggest that any beneficial effects may take several months to become apparent and might not occur in all types of dystonia associated with CP. virginia.edu

A retrospective study of 101 children with CP treated with this compound for dystonia and/or sialorrhea found that the majority tolerated the medication well and showed improvements. nih.gov Conversely, another systematic review suggested that this compound results in little to no difference in dystonia and motor function in children with CP. frontierspartnerships.org

Sialorrhea (Drooling) in Pediatric and Adult Populations

This compound's anticholinergic effects lead to a decrease in saliva production, making it a treatment option for sialorrhea (excessive drooling). parkinsons.org.ukparkinson.org This can be a significant issue for both children and adults with neurological conditions such as cerebral palsy and Parkinson's disease. pediatriconcall.comparkinson.org

In pediatric populations, particularly those with cerebral palsy, this compound has been used off-label to manage drooling. pediatriconcall.com A systematic review of anticholinergic treatments for sialorrhea in children found that this compound, among other agents, has shown efficacy. nih.gov One study reported improvement in drooling in 33% to 85% of children treated. nih.gov

For adults with Parkinson's disease, where drooling can be a troublesome symptom, anticholinergic medications like this compound can help by reducing saliva production. parkinsons.org.ukparkinson.org

Potential in Huntington's Chorea and Spasmodic Torticollis

Huntington's Chorea: Research into the use of this compound for Huntington's chorea is limited. While the core pathology of Huntington's involves different neurotransmitter systems than those primarily targeted by this compound, the complex nature of movement disorders sometimes leads to empirical trials of various agents.

Spasmodic Torticollis (Cervical Dystonia): This is a focal dystonia affecting the neck muscles. researchgate.net this compound has been shown to be an efficacious treatment for this condition. researchgate.net However, studies comparing it to botulinum toxin injections suggest that botulinum toxin provides more reliable symptomatic relief with fewer adverse effects. researchgate.net Anticholinergic drugs like this compound are often used orally in the management of spasmodic torticollis. cambridge.org

Organophosphate Poisoning and Cholinergic Crisis

This compound has been investigated as a countermeasure for poisoning by organophosphorus (OP) compounds, which are found in pesticides and chemical nerve agents. researchgate.net These agents inhibit the enzyme acetylcholinesterase (AChE), leading to an excess of the neurotransmitter acetylcholine and resulting in a life-threatening cholinergic crisis. researchgate.net

Preclinical studies have indicated that this compound may be more effective than atropine, a standard antidote, in counteracting the severe effects of OP-induced acetylcholinesterase inhibition, such as cholinergic crisis and seizures. researchgate.netnih.govnih.gov The enhanced efficacy of this compound was initially thought to stem from its ability to cross the blood-brain barrier and block not only muscarinic acetylcholine receptors (mAChRs) but also N-methyl-D-aspartate (NMDA) receptors, which are involved in the seizure activity that follows OP exposure. nih.govnih.gov Seizures following OP exposure are initiated by muscarinic receptor overstimulation but are sustained by glutamatergic hyperexcitation, which is a primary cause of brain damage. researchgate.net

Further research has revealed a more complex mechanism. Studies have demonstrated that this compound can suppress synaptic transmission through a pathway independent of its action on mAChRs, NMDA receptors, and α7 nicotinic receptors (nAChRs). nih.govnih.gov This suggests that its ability to inhibit action potential-dependent synaptic transmission may be a key factor in its effectiveness against OP intoxication. nih.gov In addition to these actions, the anticonvulsant effects of this compound in the context of poisoning by the nerve agent soman may also be partially linked to its influence on the striatal dopaminergic system. nih.gov Case reports have documented the use of this compound in treating neurological complications, such as extrapyramidal syndrome, that can arise during the intermediate phase of recovery from organophosphate poisoning. mums.ac.irmums.ac.ir

Table 1: Mechanistic Profile of this compound in Organophosphate Poisoning

| Reported Efficacy | More effective than atropine in countering OP-induced seizures and neuropathology in preclinical studies researchgate.netnih.govnih.gov | Standard treatment, but may be less effective against CNS effects nih.gov |

Influence on Glioblastoma Growth

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, known for its rapid growth and resistance to therapy. nih.govresearchgate.netnih.gov Recent preclinical studies have explored the repurposing of existing drugs, including this compound, as a potential therapeutic strategy for this challenging cancer. nih.govfrontiersin.org A key advantage of this compound is its high permeability across the blood-brain barrier, allowing it to reach tumors within the brain. nih.govfrontiersin.org

Research has shown that this compound can target and inhibit the proliferation and survival of glioblastoma stem cells (GSCs), which are thought to drive tumor growth and recurrence. researchgate.netmdpi.comtandfonline.com In vitro studies have confirmed the therapeutic potential of this compound, demonstrating its ability to effectively suppress the growth, proliferation, and survival of mesenchymal-subtype glioblastoma (MES-GBM) cells, which are particularly aggressive and therapy-resistant. nih.govresearchgate.netnih.gov These effects were observed with limited impact on non-cancerous cells. nih.govresearchgate.netnih.gov

Table 2: Research Findings on this compound's Effect on Glioblastoma Cells

| General Effect | Suppresses growth, proliferation, and survival of GBM stem cells | Classical and Mesenchymal Subtypes | nih.govresearchgate.netnih.gov |

Levodopa Absorption and Efficacy

This compound's anticholinergic action can delay gastric emptying. drugs.com This delay can lead to increased gastrointestinal degradation of Levodopa, thereby decreasing its absorption and reducing its peak serum concentrations. drugs.comnih.gov Studies have indicated that this interaction can diminish the therapeutic efficacy of Levodopa in some patients. nih.gov Research in both rats and humans has shown that the concurrent administration of this compound can decrease plasma levels of orally administered Levodopa. nih.gov One study reported a 16% to 20% reduction in Levodopa's peak serum concentrations when co-administered with this compound. drugs.com This reduction in absorption may necessitate adjustments in Levodopa dosage to maintain optimal therapeutic outcomes. medscape.comdrugs.com

Potentiation of Levodopa's Dopaminergic Effects

Despite the potential for reduced absorption, some clinical observations suggest that this compound can enhance the therapeutic effects of Levodopa in certain contexts. medscape.com This potentiation may be particularly beneficial for controlling tremor, a symptom that can be resistant to Levodopa monotherapy. cambridge.orgresearchgate.net However, the mechanisms underlying this potentiation are not fully understood and may involve complex interactions within the basal ganglia circuitry. A study in hemiparkinsonian monkeys demonstrated that the combination of this compound and a Levodopa ester initially produced a potentiated effect, although this effect diminished over time. nih.gov

Exacerbation of Dyskinesia with Levodopa

A significant concern with the concomitant use of this compound and Levodopa is the potential to increase drug-induced involuntary movements, or dyskinesias. drugs.comrxlist.com While Levodopa itself is a primary cause of dyskinesias in long-term Parkinson's disease treatment, the addition of an anticholinergic agent can exacerbate these movements. medscape.comtg.org.au This may require a reduction in the dosage of either or both drugs to manage these motor complications effectively. drugs.com

Linear Synthesis

The linear synthesis of this compound is a sequential process that builds the molecule step-by-step. iiab.mewikipedia.org A common approach begins with the aminomethylation of acetophenone. iiab.mewikipedia.orgneu.edu.tr This initial step involves the reaction of acetophenone with paraformaldehyde and piperidine, which undergoes a Mannich reaction to form the intermediate, 2-(1-piperidino)propiophenone. iiab.mewikipedia.orggpatindia.com Subsequently, this intermediate is subjected to a Grignard reaction with cyclohexylmagnesium bromide to yield the final this compound molecule. iiab.mewikipedia.orgneu.edu.tr

Mannich Reaction and Grignard Reaction in Synthesis

The Mannich and Grignard reactions are cornerstone transformations in the synthesis of this compound. iiab.mewikipedia.org The Mannich reaction is a three-component condensation that forms a β-amino carbonyl compound, which is a key structural motif in many pharmaceuticals, including this compound. derpharmachemica.comipinnovative.comnih.govhumanjournals.com Specifically, it is used to introduce the piperidine-containing side chain onto the propiophenone backbone. neu.edu.trgpatindia.com

The subsequent Grignard reaction is a powerful carbon-carbon bond-forming reaction. In the synthesis of this compound, a Grignard reagent, cyclohexylmagnesium bromide, is used to introduce the cyclohexyl group to the carbonyl carbon of the previously formed Mannich base. iiab.mewikipedia.orgneu.edu.tr This reaction is critical for creating the tertiary alcohol that is a key feature of the final molecule. Recent advancements have explored the use of solvents like methyl tert-butyl ether (MTBE) to improve the safety and stability of the Grignard reaction by allowing for milder reaction temperatures.

Importance of Heterocyclic or Carbocyclic R1/R2 Groups

For anticholinergic activity in this class of compounds, the presence of either heterocyclic or carbocyclic groups at the R1 and R2 positions is crucial. gpatindia.comgpatindia.com In this compound, these positions are occupied by a phenyl group and a cyclohexyl group. iucr.org Studies on analogs have shown that modifications to these rings can significantly impact activity. For instance, replacing the cyclohexyl ring with another benzene ring tends to decrease the affinity for the dopamine transporter. lookchem.comresearchgate.netnih.gov The nature of these bulky lipophilic groups is a key determinant of the compound's interaction with its target receptors.

Role of X (Oxygen or Absence)

A critical feature of the this compound molecular structure is the presence of a hydroxyl (-OH) group, where oxygen (X) is a key component. This hydroxyl group is considered a typical stereochemical feature essential for its pharmacological activity. iucr.org The oxygen atom, being electron-donating, plays a significant role in the molecule's ability to interact with its receptor. iucr.org

Impact of N-Substituent (Quaternary Ammonium Salt, Tertiary Amine, Alkyl Groups)

The nitrogen atom within the piperidine ring of this compound is another key pharmacophoric element. Modifications to this site, known as the N-substituent, have a profound impact on the compound's activity. This compound itself is a tertiary amine.

General SAR principles for this class of compounds show that the N-substituent can be a tertiary amine or can be converted into a quaternary ammonium salt. gpatindia.comgpatindia.com Quaternization of the nitrogen, for example by creating a methiodide derivative, involves adding an additional alkyl group (like a methyl group) to the nitrogen, giving it a permanent positive charge. This modification often affects the compound's potency and its ability to cross the blood-brain barrier.

Studies on this compound methiodide, a quaternary ammonium salt, have been instrumental in understanding receptor interactions. For instance, research has shown high stereoselectivity for both the tertiary amine (this compound) and its quaternary salt at various muscarinic receptor subtypes. nih.gov The size of the alkyl groups on the nitrogen also influences receptor selectivity. Increasing the bulk of the N-substituent can alter the affinity for different receptor subtypes. For example, in adrenergic agents, increasing the bulk of the nitrogen substituent tends to decrease α-receptor activity while increasing β-receptor activity. While a different receptor system, this illustrates the general principle of how N-substituent size can modulate receptor selectivity.